Natural Vitamin D Vs Synthetic Vitamin D

Introduction

An UV-B (290–315 nm)-dependent, nonenzymatic reaction in human skin converts the cholesterol precursor 7-dehydrocholesterol into previtamin D3 that further isomerizes into vitamin D3 (calciferol, 1) (1) (Figure 1). Similarly, UV-B-radiated plants and mushrooms are able to produce the isomer vitamin D2 (ergocalciferol, 2) based on their membrane sterol ergosterol. (2) Both secosteroids are themselves biologically inert and have to be activated by hydroxylation first at C-25, leading to the prehormones 25-hydroxyvitamin D3 [25(OH)D 3 , (calcidiol, 3)] and 25(OH)D2 , and then at C-1, creating 1,25(OH) 2 D 3 (calcitriol, 4) (3) and 1,25(OH)2D2 , respectively.

Figure 1

Figure 1. Vitamin D metabolites and analogs available on the market.

25(OH)D 3 is the metabolically most stable and abundant vitamin D metabolite, and its serum levels serve as a biomarker of the vitamin D status of individuals. (4) The biologically active form of vitamin D3, 1,25(OH) 2 D 3 , acts via activation of the transcription factor VDR as a nuclear hormone that directly affects gene regulation. (5) The physiological role of vitamin D is the regulation of calcium homeostasis for maintaining bone mineralization (6) as well as the modulation of innate and adaptive immunity (7) for improving the response to infections by microbes, such as Mycobacterium tuberculosis, (8) and preventing autoimmune diseases, such as multiple sclerosis. (9)

Lifestyle decisions, such as staying predominantly indoors and covered by textile outdoors, combined with changes in seasons and climate cause, for many individuals, insufficient exposure to UV-B and thus low endogenous production of vitamin D3. Human diet is often rather low in vitamin D because only fatty fish and UV-B irradiated mushrooms have reasonable quantities of the vitamin D3 or vitamin D2, respectively. The fortification of milk, margarine, and juices with vitamin D3 or vitamin D2 is applied in some countries. Moreover, in winter months daily supplementation with at least 25 μg (1000 IU) of vitamin D3 is recommended in order to prevent vitamin D deficiency. (10) The latter not only would result in rickets in children and in a higher risk of bone fractures due to osteoporosis or osteomalacia in adults, (11) but also will compromise the function of the immune system and the claimed preventive actions of vitamin D against cardiovascular diseases, diabetes, neuropsychiatric disorders, and cancer. (12) Supplementation with vitamin D3 clearly increased in the general population, e.g., the sales of vitamin D supplementation products increased within 1 decade nearly 15-fold. (13)

There is no doubt that a sufficient vitamin D status is important for bone health, (14) but overdosing with vitamin D3, 1,25(OH) 2 D 3 , or its synthetic analogs may result in tissue calcification. (15) Symptoms of hypercalcemia are (i) digestive distress, such as vomiting, nausea, and stomach pain, (ii) fatigue, dizziness, and confusion, (iii) excessive thirst, and (iv) frequent urination. However, hypercalcemia occurs rarely and no other severe side effects or toxicity of vitamin D overdosing is known. Nevertheless, higher doses of vitamin D3 are not recommended as nutritional supplement for reaching nonskeletal effects of the vitamin. Similarly, the main goal of the development of vitamin D analogs is to identify compounds with a low calcemic effect versus a potent antiproliferative, prodifferentiating, and/or immune-modulatory function.

In total, more than 3000 synthetic vitamin D analogs were developed by various pharmaceutical companies and academic research groups in order to advance the biological properties of the natural compound for a applications in the therapy of (i) hyperproliferative diseases, such as different types of cancer, (ii) psoriasis, an autoimmune disease of the skin, (16) or (iii) bone disorders, such as osteoporosis. (17) However, so far only a few vitamin D compounds made it to the market (Table 1). In addition to vitamin D3 being extensively used as a nutritional supplement, the commercially most successful vitamin D analog is calcipotriol (5), which is topical agent in clinical use for the treatment of psoriasis. Together with the compounds doxercalciferol (6), alfacalcidol (7), tacalcitol (8), paricalcitol (9), oxacalcitriol (10), falecalcitriol (11), and eldecalcitol (12) it had been discussed in previous reviews (18,19) (Figure 1). In contrast, despite promising in vitro results, analogs such as inecalcitol (13) or seocalcitol (14) were unsuccessful in phase II clinical trials of acute myeloid leukemia (www.hybrigenics.com/news/articles/list/type/2) or pancreatic cancer, (20) respectively. Interestingly, some immune-system-related vitamin D target genes, such as cathelicidin antimicrobial peptide (CAMP) and CD14 (encoding for a Toll-like receptor 4 co-receptor), are very responsive, (21,22) while there are no vitamin D target genes with comparable inducibility involved in the management of cellular growth and differentiation. The failure of anticancer trials and the success in the therapy of an immune disease as well as prominent gene regulatory effects in immune cells suggest that VDR ligands, in addition to bone-related functions, may rather have a therapeutic potential in immune diseases than in cancer.

Table 1. Vitamin D Compounds on the Marketa

The majority of synthetic VDR ligands are direct derivatives of 1,25(OH) 2 D 3 , but within the past years an increasing number of vitamin D mimics were published. 1,25(OH) 2 D 3 had been modified at its side-chain, A-ring (often together with side-chain changes), triene system, and C-ring. These modifications follow the strategy to increase the VDR binding affinity while in parallel modulating the metabolic stability of the molecules. (18) A reasonable number of new vitamin D analogs have been published within the past years and will be discussed in this review. Moreover, the number of solved VDR crystal structures with synthetic ligands has significantly grown.

Central Role of VDR in Vitamin D Signaling

VDR is the only protein expressed by the human genome that is able to bind 1,25(OH) 2 D 3 and its analogs at subnanomolar concentrations. (23) Thus, all physiological functions of vitamin D compounds are mediated by VDR and its target genes. (24) The VDR gene is expressed most prominently in intestine, kidneys, and bone, but in most of the other 400 human tissues and cell types some VDR expression is found. (25) This means that not only tissues that relate to calcium homeostasis and bone formation but also immune cells respond to vitamin D. (26)

VDR is an endocrine receptor and member of the superfamily of nuclear receptors; i.e., the mechanisms of its action are comparable to the receptors for glucocorticoids and estrogen. (27) VDR's ligand-binding domain (LBD) is structurally conserved and comprises 11–15 α-helices, modestly varies between solved crystal complexes, and depends on the folding of the intrinsically disordered region between helices H1 and H3 and the presence of a helix HX between helices H11 and H12 (28,29) (Figure 2A). The lower part of the LBD contains a ligand-binding pocket (LBP), which is a cavity with a volume of ∼700 Ã…3 (with possible expansion beyond 1000 Ã…3) being formed by some 40 mostly nonpolar amino acids. (30) Three pairs of polar amino acids within the LBP fix via hydrogen bonds each one of the three OH groups (at C-1α, C-3β, and C-25) of 1,25(OH) 2 D 3 . The 1α-OH group interacts with Y143 (helix H1) and S278 (helix H5), the 3β-OH group contacts S237 (helix H3) and R274 (helix H5), and the 25-OH group interferes with H305 (loop between helices H6 and H7) and H397 (helix H11) (28) (Figure 2B).

Figure 2

Figure 2. 1,25(OH) 2 D 3 complexed to the VDR-LBD. The VDR-LBD has a conserved 3D architecture, which is made of a three-layer α-helical sandwich. In the lower part of the LBD the LBP is located. All the helices are labeled from N-terminus toward C-terminus and numbered in white color (A). Details on the LBP with bound 1,25(OH) 2 D 3 and critical amino acids that provide anchoring contacts for the three OH groups (B). Details on the conformation of the bound 1,25(OH) 2 D 3 molecule with the annotated OH groups and highlights to its contribution of its activity. The numbering of the carbons atoms is indicated (C). The figure is based on the PDB code 1DB1.

VDR ligands induce a conformational shift to the LBD, which replaces co-repressor proteins by coactivator proteins; i.e., ligand binding induces a different protein–protein interaction profile of the receptor. (31) VDR agonists cause an efficient dissociation of co-repressors from the LBD and allow the specific binding of coactivators and the mediator complex (Figure 3). Coactivators also attract chromatin modifying enzymes that write, erase, or read post-translational marks of histones, such as acetyl and methyl groups, to histone proteins of nucleosomes in the vicinity of genomic VDR binding sites. (32) Moreover, also members of chromatin remodeling complexes interact in a ligand-dependent fashion with VDR and cause a rearrangement of nucleosomes at vitamin D-sensitive chromatin regions. (33) These epigenetic changes allow looping of VDR-bound enhancers toward accessible transcription start sites (TSSs) at hundreds to thousands of loci throughout the human genome. (34) These enhancer-TSS assemblies are triggered by ligand-activated VDR and finally result in an increase or decrease in the expression of hundreds of primary vitamin D target genes (Figure 3).

Figure 3

Figure 3. Vitamin D signaling. 25(OH)D 3 is converted by the enzyme CYP27B1 to its biologically most active form 1,25(OH) 2 D 3 , which binds to the transcription factor VDR. Upon binding of 1,25(OH) 2 D 3 or synthetic agonists, a conformational change in the LBD is induced leading to cofactor exchanges shifting the balance toward recruitment of coactivator proteins. Co-repressor proteins dissociate from the VDR-RXR heterodimer. In parallel, the mediator complex and chromatin modifying enzymes (readers, writers, and erasers) are recruited in order to handle histone proteins of local nucleosomes around genomic VDR binding sites. In addition, chromatin remodeling complexes are recruited and rearrange nucleosomes at vitamin D-sensitive chromatin regions. Altogether, these chances lead to looping of the distal regulatory elements toward the basal transcriptional machinery with RNA polymerase II and other nuclear adaptor proteins initiating the start of 1,25(OH) 2 D 3 -dependent transcription from hundreds to thousands of TSS regions throughout the whole human genome. The ultimate outcome is the increase or decrease of the of primary vitamin D target gene expression followed by changes of indicated cellular functions.

The structure of the human VDR-LBD complexed with 1,25(OH) 2 D 3 was solved in the year 2000. (28) Since then altogether 143 human, rat, and zebrafish VDR-LBDs have been crystallized with a large number of synthetic analogs (35) (Table S1). In general, the analogs behave like 1,25(OH) 2 D 3 by stabilizing the LBD in more or less the same conformation, since the three OH groups of each vitamin D compound take up a nearly identical position. This suggests that there is only one agonistic conformation of the LBD for which the interaction between the ligand's 25-OH group and the LBP amino acids H305 and H397 are most important (Figure 2C).

On the basis of the vitamin D analog's chemical modification, all solved VDR-ligand-complexes can be divided to the six groups: (i) A-ring modifications, (ii) side-chain modifications, (iii) triene system modifications, (iv) combined A-ring and side-chain modification, (v) modifications in the CD-ring, and (vi) nonsteroidal analogs. All modifications aim to either (i) maintain the three anchoring OH groups at the same position as in 1,25(OH) 2 D 3 and/or (ii) fill the LBP most efficiently in order to form additional hydrogen network and/or hydrophobic contacts. More variant modifications of 1,25(OH) 2 D 3 aim to alter the ligand conformation or to bounce the shape of the LBP by adding an additional side-chain at positions C-20 or C-22. Moreover, de novo designed nonsteroidal compounds carry modifications, such as the exchange the classical secosteroid ring structure by rings with aromatic character. The aim with these molecules is to maintain the hydrophobic interactions with amino acid residues lining the inner surface of the LBP as well as to increase the stacking interaction with aromatic amino acid residues.

In this review we discuss different classes of vitamin D analogs and, where applicable, provide molecular understanding from VDR crystal structures.

Side-Chain Modifications

The first locked side-chain vitamin D analogs nor-21-20(22),23(24)-diyn-1,25(OH)2D3 (15), nor-21,23,24,25,26,27-20(22)-yn-22-(3-hydroxyphenyl)-1,25(OH)2D3 (16a), nor-21,23,24,25,26,27-20(22)-yn-22-[3-(hydroxymethyl)phenyl]-1,25(OH)2D3 (16b), and nor-21,23,24,25,26,27-20(22)-yn-22-[4-(hydroxymethyl)phenyl]-1,25(OH)2D3 (16c) have been synthesized by convergent route through a Wittig–Horner approach starting from Inhoffen–Lythgoe diol (36) (Figure 4). These analogs lead to significant activation of VDR-dependent transcription in comparison to 1,25(OH)2D3 . An unique structural modification on the C-22-diyne analog, a C-17-methyl substitution, was provided through a vinyl(pinacolo)boronate approach and resulted in the C-17-methyl-substituted vitamin D analogs nor-21-20(22),23(24)-diyn-17-methyl-1,25(OH)2D3 (17a) and nor-21-20(22),23(24)-diyn-17-methyl-26,26,26,27,27,27-hexafluoro-1,25(OH)2D3 (17b). (37) The C-22-aromatic-substituted analogs are less potent in activating VDR than the C-22-diyne isomers. The C-17-methyl analogs bind more efficiently to VDR than 1,25(OH) 2 D 3 .

Figure 4

Figure 4. Side-chain-modified vitamin D analogs. The table summarizes the biological properties of the compounds: reference, 1,25(OH) 2 D 3 ; (=) similar value; (+) >10× higher; (++) >100× higher; (+++) >1000× higher; (−) >10× lower; VDR aff, VDR affinity; Prolif inh, proliferation inhibition; Transac act, VDR transactivation activity; calcemia, [Ca2+] level changes in serum.

The two side-chain analog Gemini comprises an unaltered side-chain of 1,25(OH) 2 D 3 and a second chain at C-20. (38,39) Although the volume of Gemini is increased by some 25%, it still fits into VDR's LBP. (30) One side-chain of Gemini takes the same place as that of 1,25(OH) 2 D 3 , whereas an extra subcavity opens within the LBP for the second side-chain. (40) The increase in transcriptional activity of Gemini (41) motivated the preparation of Gemini-type analogs with side-chains containing double or triple bonds and isohexafluoro-2-propanol or isohexadeutero-2-propanol side-chain ends. Compounds 18–20 have been synthesized with both configurations at C-20 by a convergent approach through Wittig–Horner coupling starting from Inhoffen–Lythgoe diol. (42) (R)-Analogs showed higher antiproliferative potency in MCF10CA1 human breast cancer cells than their (S)-counterparts, and both were 100–1000 times more potent than 1,25(OH) 2 D 3 . Furthermore, both configurations of the Gemini derivatives are also more potent than 1,25(OH) 2 D 3 in inducing the differentiation of NB4 human leukemia cells. Thus, Gemini compounds have enhanced potency in inhibiting proliferation and inducing differentiation with reduced induction of hypercalcemia when compared to 1,25(OH) 2 D 3 . Moreover, C-20 methyl-substituted Gemini analogs (21–23) are also potent in the inhibition of HL-60 human leukemia cell proliferation and the induction of CAMP gene expression. (43)

1α-Hydroxy-25,26,27-trinor-24-o-carboranyl-vitamin D3 (1,25cD 3 , 24, Figure 4) is a rather new vitamin D analog, in which an o-carborane moiety replaces the 25-OH group. (44) Despite the lack of this critical group, 1,25cD 3 is as effective as 1,25(OH) 2 D 3 in inhibiting the growth of MCF-7 human breast cancer cells and in inducing the differentiation of HaCaT human keratinocytes. VDR binds 1,25cD 3 2 times tighter than 1,25(OH) 2 D 3 and is equally potent as the natural hormone in inducing reporter gene activity while not showing adverse calcemic effects. Moreover, like most other vitamin D analogs, the conformation of the complex of 1,25cD 3 with VDR's LBD is highly similar to that of 1,25(OH) 2 D 3 ; i.e. the protein shows the same topology. Nevertheless, the loop between helices H6 and H7, which is a critical region for the activation of the receptor, and the last part of helix H11 show shifts by 0.6 Å. The carborane side-chain is 2.4 Å longer than that of 1,25(OH) 2 D 3 , but it is hydrophobic and therefore favors the interaction with hydrophobic amino acid in this part of the VDR-LBP. This compensates for the loss of the 25-OH group (Figure 5A). Thus, the collection of small changes stabilizes helices H3, H11, and H12 and overall causes higher stability of VDR's LBD.

Figure 5

Figure 5. Structure–function relationship of VDR ligands (I). The carborane group of 1,25cD 3 creates additional hydrophobic interactions that compensate for the loss of the 25-OH group. All residues that have conserved interactions are shown in gray (top). Detailed interaction with residues based on PDB code structures 2HC4 (1,25(OH) 2 D 3 ) and 5E7V (1,25cD 3 ). The displayed interactions are identified under cutoff 3.5 Ã… (A). Destabilization of the VDR-LBD upon binding of 23,36-lactone analogs. Representation of crystal structure b-factors using structures PDB codes 1RK3 (1,25(OH) 2 D 3 , left) and 3A2H (TEI-9647, right). Regions with the highest b-factors are highlighted in red and they are helices H9–10 that may affect heterodimerization with RXR, helix H11 affecting the position of helix H12, and the coactivator peptide showing very high b-factors overall. The most stabile part of the VDR is shown in blue through green, yellow and red monitoring the highest b-factor values (B). Structural implication of 22S-alkyl-2-methylene-19-nor-1,25(OH)2D3 binding. The position of the helix H12 takes the same conformation in both 22S-alkyl-2-methylene-19-nor-1,25(OH)2D3 and 1,25(OH) 2 D 3 . Many residues around the two aliphatic chains move or rotate, such as H301 (loop helices H6/7), H393 (helix H11), or F418 (helix H12). Structural elements from 22S-alkyl-2-methylene-19-nor-1,25(OH)2D3 (PDB code 2ZXM) and 1,25(OH) 2 D 3 (PDB code 1RK3) complexes are highlighted in green and white color, respectively (C).

A-Ring Modification

The biological profiles of the C-2-substituted vitamin D analogs 2-(3′-hydroxypropyl)-1,25(OH)2D3 (25), 2-butyl-1,25(OH)2D3 (26), 2-(4′-hydroxybutyl)-1,25(OH)2D3 (27), 2-(2′-hydroxyethoxy)-1,25(OH)2D3 (28), 2-(3′-hydroxypropoxy)-1,25(OH)2D3 (29), and 2-(4′-hydroxybutoxy)-1,25(OH)2D3 (30) (Figure 6) indicated that C-2β-substituted analogs have higher affinity for the serum vitamin D binding protein (DBP) and lower affinity for VDR but are superior to C-2α analogs in reporter gene assays. (45)

Figure 6

Figure 6. Vitamin D analogs with A-ring modifications. The table summarizes the biological properties of the compounds: reference, 1,25(OH) 2 D 3 ; (=) similar value; (+) >10× higher; (−) >10× lower; (--), >100× lower; VDR aff, VDR affinity; 24OH trans, CYP24A1 transactivation activity; HL60 diff, HL-60 cell differentiation induction.

The analog 2-(3′-hydroxypropyl)-1α-methyl-25(OH)2D3 (32) was synthesized through a Pd-catalyzed ring-closure of enyne, and coupling with vinyl bromide and showed a 2-fold higher potency than 1,25(OH) 2 D 3 in reporter gene assays. (46) Interestingly, when VDR's amino acid R274, which contacts the 1α-OH group of the ligand (Figure 2), is mutated to a hydrophobic residue (R274L), the compound is even 7 times more potent than the natural hormone, suggesting that the 1α-methyl group is stabilized primarily by hydrophobic interactions.

The compounds 1α,4α,25(OH)3D3 (33a) and 1α,4β,25(OH)3D3 (33b) were created through a Pd-catalyzed ring-closure and coupling and showed lower affinity for VDR than 1,25(OH) 2 D 3 . (47) However, the 4β-analog (33b) displays higher VDR affinity and potency in reporter gene assays than the 4α-compound (33a).

The analogs 2-methylene-25-(OH)D3 (34a) and 2-methylen-20-epi-25-(OH)D3 (34b) belong to the family of the potent lead compound 2-methylene-1,25(OH)2D3 (35, 2MD) and were synthesized through a Pd-catalyzed coupling between an enol triflate and an enyne. (48) These molecules are defined by the relocation of the exocyclic methylene group from C-10 to C-2 and the inversion of the C-20 configuration. Compound 34a shows lower affinity for VDR than 1,25(OH) 2 D 3 , lower potency in inducing HL-60 cell differentiation and in reporter gene assays, while compound 34b displays the same affinity for VDR as 1,25(OH) 2 D 3 , higher potency in HL-60 cell differentiation induction, and lower activity in reporter gene assays.

Triene System Modifications

The compounds PRI-1731 (36), PRI-1732 (37), PRI-1733 (38), and PRI-1734 (39) represent a series of vitamin D analogs with a branched side-chain (E)-stereochemistry at the C-5/C-6 double bond, both configurations at C-24 and a C-22/C-23 double bond or an OH group at C-22 (49,50) (Figure 7). They have moderate prodifferentiating activities on HL-60 cells and their maximal inhibition of proliferation ranged from 10% to 15% of that for 1,25(OH) 2 D 3 and 20–30% of that for 1,25(OH)2D2.

Figure 7

Figure 7. Triene system modified vitamin D analogs.

Side-Chain and A-Ring Modifications

25-Dehydro-1α-hydroxy-vitamin D3-26,23 lactones with double modifications of C-24 and C-2α were synthesized via a convergent approach by Pd-catalyzed ring closure of a enyne and subsequent coupling with a functionalized vinyl bromide. (51,52) Numerous analogs have been synthesized with variations in their C-23 configuration, C-24 mono- or disubstitution [H, Me, Et, c-Pr, n-Pr, n-Bu, i-Bu (40, 41, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72)] and C-2α substitution [H, Me, CH2CH2CH2OH, OCH2CH2CH2OH, (42–47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73)] (Figure 8). The principal characteristic of these analogs is their antagonist activity, probably due to locking the VDR-LBD in a conformation where it does not effectively interact with coactivator proteins. This can be seen also from the values of the β-factors found in the crystal structure (PDB code 3A2H) of the lactone analog TEI-9647, where the coactivator peptide shows very high values compared to 1,25(OH) 2 D 3 . In addition, helices H9 and 10 as well as H11 and to some extent H12 show higher fluctuation leading to overall destabilization of the LBD (Figure 5B). Structure–activity relationship studies demonstrated that the exomethylene group of the lactone is indispensable, the C-23S configuration provides higher activity, and an appropriate combination of C-24 and C-2α substitution obtains the highest antagonist potency.

Figure 8

Figure 8. Vitamin D analogs with side-chain and A-ring modifications (I). The table summarizes the biological properties of the compounds: reference, 1,25(OH)2D3 ; (=) similar value; (+) >10× higher; (++) >100× higher; (−) >10× lower; (--) >100× lower; VDR aff, VDR affinity; Antag act, antagonistic activity.

19-nor (74) and 1α-F (75) Gemini analogs containing triple bonds and isohexafluoro-2-propanol or isohexadeutero-2-propanol side-chain end groups (42) (Figure 9) were synthesized. Again (R)-analogs are more potent in inhibiting MCF10CA1 cell proliferation than their (S)-counterparts. Both isomers are active already at 100–1000 times lower concentrations than 1,25(OH) 2 D 3 . In both configurations the Gemini analogs are equally potent to 1,25(OH) 2 D 3 in inducing NB4 cell differentiation but are less calcemic than the natural hormone.

Figure 9

Figure 9. Vitamin D analogs with side-chain and A-ring modifications (II). The table summarizes the biological properties of the compounds: reference, 1,25(OH)2D3 ; (=) similar value; (+) >10× higher; (++) >100× higher; (+++) >1000× higher; (−) >10× lower; (--) >100× lower; VDR aff, VDR affinity; MCF10 prol, MCF10 cell proliferation inhibition; NB4 diff, NB4 cell differentiation induction; MG63 trans, MG63 cell transactivation activity; U963 prol, U963 cell proliferation inhibition; HL60 diff, HL-60 cell differentiation induction.

A series of 2-methylene-19-nor vitamin D analogs with or without C-22S alkyl substitution, such as 2-methylene-19,25,26,27-tetranor-vitamin D3 (76), 2-methylene-19,25-dinor-vitamin D3 (77), 2-methylene-19,26,27-trinor-vitamin D3 (78), and 2-methylene-19-nor-vitamin D3 (79) and their C-22S alkyl derivatives (a, R = H; b, R = Et; c, R = Bu) have been prepared and biologically tested. (53) The side-chain modifications in 76, 77, and 78 reduce the VDR binding affinity 10-fold compared to 1,25(OH) 2 D 3 . Interestingly, an increasing size of the C-22 substituent in 2-methylene-19-nor-vitamin D3 (79) results in a decreased VDR binding affinity compared to 1,25(OH) 2 D 3 . Compounds with a normal side-chain (79a, 79b, and 79c) show strong activation in reporter gene assays and compounds without C-22 substitution (76a, 77a, 78a, and 79a) even full agonist activity. In contrast, C-22S butyl-substituted molecules (76c, 76c, 78c, and 79c) present little transactivation potency, while C-22S ethyl-substituted compounds (76b, 77b, 78b, and 79b) display intermediate activity. Moreover, the analogs 76a, 77a, 78a, and 79a induce the recruitment of the VDR partner receptor retinoid X receptor (RXR, Figure 3) and of a coactivator peptide in a concentration dependent manner, while C-22S-substituted compounds cause only moderate effects.

VDR-LBD crystal structures complexed with further 22S-alkyl-2-methylene-19-nor-1,25(OH)2D3 derivatives (80–83) (54) confirmed that the compounds trigger the creation of an extra cavity of the LBP by rotating L305 about 27° outward, in order to shelter the butyl group (Figure 5C). Ligands act as VDR antagonists when they do not interact with the C-terminal helix H12 of the receptor. Interestingly even though the position of helix H12 is maintained in the agonistic position, most likely forced by the presence of the coactivator peptide, there is a shift or rotation of multiple residues away from the 22-butyl analog. These changes weaken the interaction with H301 (loop H6/7), H393 (H11), or F418 (H12) and destabilize this region of the LBD (Figure 5C). Interestingly, in the presence of a coactivator peptide some of the antagonistic 22-butyl analogs take the agonistic conformation. Whether this is a technical artifact of the crystallization or has a physiological meaning, such as sensing of cofactor balance in the cellular context, needs to be clarified.

20-epi-Eldecalcitol (84), a 20-epi derivative of the antiosteoporotic drug eldecalcitol (12) (Table 1 and Figure 1), was synthesized through a convergent approach by Pd-catalyzed ring-closure of an enyne and coupling with vinyl bromide. (55) Since 20-epi-1,25(OH)2D3, a diasteromer of 1,25(OH) 2 D 3 possessing an inverted C-21 methyl-substituent at C-20, shows enhanced biological activities compared to 1,25(OH) 2 D 3 , compound 84 displays a 50-fold increased inhibition of U937 human leukemia cell proliferation. (56)

Since the presence of a 1α-OH group in 1,25(OH) 2 D 3 is crucial for VDR binding, its replacement with a 1β-OH group [1β,25(OH)2D3, 86] causes loss of physiological activity (57) (Figure 10). Replacing the 1α-OH group with one fluor atom [1α-F,25(OH)2D3, 87] also markedly diminishes biological activity, (58) while a compound with each a fluorine atom at C-1 and C-25 [1,25(F)2(OH)2D3, 88] is devoid of all activity. (59) Interestingly, the 3-OH group is not necessary if the 1α-OH group is already in position, but the lack of the 3-OH group [1α,25(OH)2-3-deoxy-D3, 89] reduces the biological activity. (60,61) Additional methyl groups at C-1β [1β-methyl-1,25(OH)2D3, 90] and C-3α [3α-methyl-1,25(OH)2D3, 91] significantly reduce VDR binding affinity. Switching the 3-OH group from β to α position [3-epi-1,25(OH)2D3, 92] causes a drastic reduction of physiological activity. (62) In fact, compound 92 is an intermediate of 1,25(OH) 2 D 3 degradation displaying lower VDR binding affinity and lower calcemic effects compared to 1,25(OH) 2 D 3 . Despite its decreased potency, the in vivo action of compound 92 is tissue-specific.

Figure 10

Figure 10. Vitamin D analogs with side-chain and A-ring modifications (III).

Taken together, most modifications of the A-ring result in decreased biological activity except for those modified at C-2. Therefore, a large number of C-2-substituted vitamin D analogs have been synthesized and were studied intensively for their biological activity. 2α-Substitutions [2α-methyl-1,25(OH)2D3 (93)] are more potent than 2β-substitutions [2β-methyl-1,25(OH)2D3 (92)]. (63) Elongation of the C-2-alkyl group [2α-ethyl-1,25(OH)2D3 (94) and 2α-propyl-1,25(OH)2D3 (95)] reduces VDR binding affinity and biological potency, but ω-hydroxylation restores the activity. (64) 2α-Methyl-1,25(OH)2D3 (93) is twice as calcemic as 1,25(OH) 2 D 3 . In combination with 20-epimerization [2α-methyl-20-epi-1,25(OH)2D3] VDR binding affinity increases even 12-fold. (63) 2α-(3′-Hydroxypropyl)-1,25(OH)2D3 (97) has a 3-fold increased VDR binding affinity than 1,25(OH) 2 D 3 , while 2β-(3′-hydroxypropyl)-1,25(OH)2D3 (98) is 1.4 times more potent. Terminal hydroxylation of 2α- and 2β-propoxy groups at C-2, 2α-hydroxypropoxy-1,25(OH)2D3 (99) and 2β-hydroxypropoxy-1,25(OH)2D3 (100) also increases the VDR binding potential.

19-nor-Vitamin D analogs are known to be devoid of hypercalcemic and hyperphosphatemic effects. (65,66) For example, 19-nor-1,25(OH)2D3 (101) has a 5 times reduced the VDR binding affinity compared to 1,25(OH) 2 D 3 paired with low or no bone calcification activity, while 19-nor-1,25(OH)2D2 (paricalcitol, 9, Figure 1) has similar affinity as the natural hormone. Selected modifications at the C-2 position of 19-nor-vitamin D analogs are more potent inducers of gene activity. 2β-(3′-Hydroxypropoxy)-19-nor-1,25(OH)2D3 (102) and 2α-(3′-hydroxypropoxy)-19-nor-1,25(OH)2D3 (103) have reduced potency in bone and intestine. (67) 2-Methylene-19-nor-20-epi-1,25(OH)2D3 (2MD, 35) shows VDR binding affinity comparable to 1,25(OH) 2 D 3 but a 100 times enhanced ability to mobilize calcium from bone. (68) Moreover, 2MD is 10 times more potent than 1,25(OH) 2 D 3 in activating CYP24A1 gene activity and inducing HL-60 cell differentiation. Analogs of 2MD with a shortened side-chain, such as 2MP (105) and 2MbisP (106) are able to reduce parathyroid hormone (PTH) production. (69)

The compound 19-nor-1α,2β,25(OH)3D3 (107) is as potent as 1,25(OH) 2 D 3 in intestinal calcium transport, while its epimer 19-nor-1α,2α,25(OH)3D3 (108) possesses less activity. (70) Importantly, both compounds are not calcemic. Compound 107 has higher VDR binding affinity than 108 and is more potent in inhibiting MCF-7 cell proliferation. When the 2-ethylidene group is in E-configuration (109), VDR binding affinity is 2.4-fold increased. Moreover, a 3′-hydroxypropylidene group at C-2 in E-configuration resulted in the potent compounds AGR (110) and 1AGS (111), which seem to be intestine-selective. (60)

2α-(3′-Hydroxypropyl)-19-nor-1,25(OH)2D3 (112), which is modified at both C-2 and C-10, shows a similar VDR binding affinity as 1,25(OH) 2 D 3 , displays a 36-fold higher potential in inducing HL-60 cell differentiation, and has a 500-fold higher antiproliferative potency in PZ-HPV-7 prostate cells. Its epimer 2β-(3′-hydroxypropyl)-19-nor-1,25(OH)2D3 (113) has lower VDR binding and prodifferentiation activity, but it is as potent as 110 in inhibiting prostate cell proliferation. (70,71)

Promising analogs with three different alterations in the vitamin D skeleton (the A-ring, the side-chain, and the CD-ring) are 1β-hydroxymethyl-16-ene-24,24-F2-26,27-bishomo-25(OH)2D3 (QW-1624-F2-2, 114) (72) and 1α-fluor-16-ene-20-epi-23-ene-26,27-bishomo-25(OH)2D3 (Ro-26.9228, 115). (73) In a skin cancer model compound 114 inhibits progression and molecule 115 restores bone loss, while both are not hypercalcemic.

Six new derivatives of compound 104 have been prepared by a convergent synthesis using the Wittig–Horner approach (74) in order to evaluate the influence of methyl groups at C-22 on biological activity (Figure 11). Single methylation of the (20R)-25-hydroxylated side-chain (117) did not change the VDR binding affinity in comparison to the parent compound 104. However, the addition of a 22-methyl group to the (20S)-25-hydroxylated side-chain (118) caused a much stronger effect. The 22R-compound 118a has a 2.5 times higher VDR binding affinity than 104 and is 250-fold more potent than its 22-epimer 118b. The prodifferentiation potential of an analog with a 22S-methyl group in the "natural" side-chain (20R) (116a) is 10-fold higher than that of its 22-epimer (116b), whereas in the case of "unnatural" 20S-compound the 22R-epimer (117a) is 1000 times more potent than its 22-epimer (117b) and 4-fold more potent than the parent compound 104. When two methyl groups were introduced at C-22, such as in the 20R-compound (118a) and the 20S-compound (118b), VDR binding affinity is increased compared to their parent molecules.

Figure 11

Figure 11. Vitamin D analogs with side-chain and A-ring modifications (IV). The table summarizes the biological properties of the compounds: reference, 1,25(OH)2D3 ; (=) similar value; (+) >10× higher; (++) >100× higher; (+++) >1000× higher; (−) >10× lower; (--) >100× lower; VDR aff, VDR affinity; 24OH trans, CYP24A1 transactivation activity; HL60 diff, HL-60 cell differentiation induction.

C-20-isomers of 25(OH)-2-methylene-vitamin D3 and 3-desoxy-1α,25(OH)2-2-methylene-vitamin D3 (117–120) were synthesized through a convergent approach using a Sonorogashira coupling (75) (Figure 11). The biological activities of compounds 119–122 are clearly lower than those of the parent compound 104. With the exception of the 1α-hydroxylated compounds they were also less active than 1,25(OH) 2 D 3 . Analogs without a 1α-OH group show lower VDR binding affinity, HL-60 cell prodifferentiation activity, and CYP24A1 activation than those hydroxylated at C-1. The addition of the 10-exo-methylene group improved the in vitro activity of the (20S)-1-desoxy compounds. In contrast, in the (20S)-series only VDR binding affinity augmented. The presence of the 2-exomethylene group resulted in enhanced intestinal calcium transport compared to 1,25(OH) 2 D 3 , but bone calcium mobilization was 10-fold decreased in the (20R)-series.

A large structure–function analysis of 39 Gemini derivatives (43) showed five compounds (123–127) with enhanced antiproliferative activity (Figure 12). Compound 127 was stronger than 1,25(OH) 2 D 3 in inhibiting cancer cell growth, while both were equipotent in their calcemic effect.

Figure 12

Figure 12. Vitamin D analogs with side-chain and A-ring modifications (V). The table summarizes the biological properties of the compounds: reference, 1,25(OH) 2 D 3 ; (=) similar value; (+) >10× higher; (++) >100× higher; (−) >10× lower; (--) >100× lower; VDR aff, VDR affinity; HL60 diff, HL-60 cell differentiation induction.

The Sonogashira approach was used to synthesize novel 14-epi derivatives of 19-nor-1α,25(OH)2-previtamin D3 (132) and 19-nor-1α,25(OH)2-tachysterol D3 (135). (76) Dienynic compounds (129–131) showed moderate VDR binding affinity, where the 2-methylene compound (129) has higher activity than the 2-methyl-substituted diastereomers 130 and 131. Previtamin D3 compounds (132–134) showed low VDR binding affinity. 14-epi-19-nor-tachysterol) D3 compounds displayed higher VDR binding affinity, of which 2-methylene-14-epi-19-nor-tachysterol D3 (137) is most potent. Crystal structure analysis indicated unique binding conformations. The binding of both epimers, 14-epi-2α-methyl- (PDB code 3AUQ) and 14-epi-2β-methyl-1,25(OH)2-6,7-dehydro-19-norvitamin D3 (PDB code 3AUR) is very similar in maintaining the position of the anchoring OH groups seen from the 1,25(OH) 2 D 3 complex (PDB code 1DB1). However, the modification between C-6 and C-7 provides rigidity for this region introducing an unforeseen compensation in flexibility for the CD rings. Compared to their more planar conformation in 1,25(OH) 2 D 3 , here they take a reverse V-letter conformation such as by the bending of the C ring about 9° downward. For the 2β-methyl isomer the residue L227 is closer to the ligand under 3.5 Ã… cutoff but under similar cutoff W286 seems to be closer to 1,25(OH) 2 D 3 , which is due to more planar conformation of the CD-rings (Figure 13A).

Figure 13

Figure 13. Structure–function relationship of various VDR ligands (II). The binding of 14-epi-2α-methyl- and 14-epi-2β-methyl-1,25(OH)2 -6,7-dehydro-19-norvitamin D3. The overall spatial conservation of the OH groups is maintained, but the CD-ring structure for the epimers shows higher flexibility by changing the more planar conformation in 1,25(OH) 2 D 3 to reverse V-letter shape. This is largely due to the bending of the C-ring downward. The other notable changes involve the proximal location of L227 in 2β-methyl epimer and W286 for 1,25(OH) 2 D 3 under 3.5 Ã… cutoff. Structural elements from 14-epi-2α-methyl- (PDB code 3AUQ), 14-epi-2β-methyl-1,25(OH)2-6,7-dehydro-19-norvitamin D3 (PDB code 3AUR), and 1,25(OH) 2 D 3 (PDB code 1DB1) complexes are highlighted in green, blue, and white color, respectively (A). Possible mechanism governing the potency of fluorinated analogs. The effect of a fluorinated functional group is illustrated on CF3 group in comparison with CH3 group located at the terminal carbons C-26 and C-27 of the ligand's aliphatic chain. The high electronegativity of the fluor atom has a pulling effect for the hydrophobic residues located in the proximity of the functional group (bottom), which cannot be seen for the 1,25(OH) 2 D 3 under the same 3.5 Ã… cutoff (top). However, the hydrogen bonds between the conserved histidines and the 25-OH group are maintained in both scenarios. The positions of the CF3 groups show a moderate opening about 5° with maintained distance between carbon C-26 and C-27. These changes have effect on the LBP, which is a bit smaller (middle panel) in the presence of CF 3 functional groups (B). Structural elements for the CF 3 and CH 3 groups are highlighted in orange and white color, respectively.

Side-Chain, D-Ring, and A-Ring Modifications

The synthesis of 12 analogs (138–149) of 1α,25(OH)2-16-ene-20-cyclopropylvitamin D3 relied on Wittig–Horner coupling (77) (Figure 14). These compounds have an unsaturated D-ring between C-16 and C-17 and a cyclopropyl group located at C-20. The structural diversity on the side-chain covered triple CC bonds (138–144), double CC bonds (145–147) and single CC bonds (148 and 149) together with the A-ring covered 1α,3β-dihydroxy (138, 143, 146, and 149), 19-nor (139, 142, 145, and 148), 3-deoxy-1α-hydroxy (141), and 1α-fluor-3β-hydroxy (140 and 144). The anti-inflammatory properties of these compounds were studied via analyzing the inhibition of the secretion of the cytokines interferon-γ (IFNG) and tumor necrosis factor (TNF). Most of 16-ene-20-cyclopropyl analogs inhibited IFNG with similar potency to 1,25(OH) 2 D 3 , but compound 149 was more potent. The inhibition of TNF showed wide differences, some analogs (138, 140, 143–145) failed to induce TNF inhibition, whereas analog 149 inhibited TNF more efficiently than 1,25(OH) 2 D 3 . The metabolism of 149 was studied and the stable 24-oxo metabolite 150 accumulated during metabolism. Compound 150 mediates similar induction of primary vitamin D target genes as analog 149 but has a lower calcemic activity.

Figure 14

Figure 14. A-ring, D-ring, and side-chain modified vitamin D analogs. The table summarizes the biological properties of the compounds: reference, 1,25(OH) 2 D 3 ; (=) similar value; (+) >10× higher; (+++) >1000× higher; (−) >10× lower; (--) >100× lower; MLR IFN-γ, INFG inhibition; LPS TNFα, TNF inhibition.

Nonsteroidal VDR Ligands

The synthesis of nonsteroidal VDR agonists containing a hydrophobic 1,12-dicarba-closo-dodecaborane (p-carborane) unit was achieved through bimolecular nucleophilic substitution (78) (Figure 15). The carborane cage replaced the CD-rings of the natural hormone exploiting the hydrophobicity of p-carborane. Despite their simple and flexible structure, the carborane-based VDR ligands show moderate binding affinity for VDR compared to 1,25(OH) 2 D 3 . The analogs are flexible acyclic triols; i.e., they lack an A-ring and conjugated triene structures. Their structures shared a branched side-chain on a carborane carbon, and in the other carbon three different chains are bound either to 3-oxaheptan-5,7-diol (151), 3-oxahexan-5,6-diol (152) or 4-oxaheptan-6,7-diol (153). The flexibility of the diol is favorable for VDR binding affinity, which, however, is more then 100 times lower than for 1,25(OH) 2 D 3 . Nevertheless, these mimics are rather active in inducing HL-60 cell differentiation [rac-151, 5%; (S)-151, 8%; (R)-151, 2%; 152, 0.05%; 153, 0.001%)]. The S-isomers showed, compared to the R-enantiomer, higher prodifferentiation activity and VDR binding affinity.

Figure 15

Figure 15. Nonsteroidal VDR ligands. The table summarizes the biological properties of the compounds: reference, 1,25(OH) 2 D 3 ; (=) similar value; (+) >10× higher; (++) >100× higher; (+++) >1000× higher; (−) >10× lower; (--), >100× lower; (---), >1000× lower; VDR aff, VDR affinity; calcemia, [Ca2+] level changes in serum; 24OH trans, CYP24A1 transactivation activity; HL60 diff, HL-60 cell differentiation induction; MCF7 pr, MCF7 proliferation inhibition.

LG190178 (154) is the first published nonsteroidal vitamin D analog. (79) In general, VDR ligands based on bisphenyl core compounds with γ-hydroxycarboxylic acid moiety (155) show agonist activity. From compounds with a fluorine-containing bisphenyl core (80) the hexafluoro analog (157) is 5 times more potent in reporter gene assays than the parent compound (155), shows 2 times higher prodifferentiation activity, and is 7 times more effective in inducing bone γ-carboxyglutamate protein (BGLAP) expression. Like in secosteroidal vitamin D analogs, fluorination is an effective modification as shown by crystal structure analysis of the VDR-LBD complexed with 155. Also in this case helix H12 is stabilized in the agonistic position allowing interaction with coactivator proteins. From physicochemical point of view the fluorine atom's ionic radius is 100% larger than that of the hydrogen, the van der Waals radius is only 27% larger. However, the high electronegativity of fluor has a possible "pulling" effect for residues residing in the nearest proximity of a fluorinated functional group. This can be illustrated on the comparison of the aliphatic chain of the ligands that have CH3 or CF3 functional groups at carbon C-26 and C-27. The latter shows additional five hydrophobic residues that cannot be seen for CH3 at the cutoff 3.5 Ã… (Figure 13B). The only maintained interactions are with conserved histidine residues. In addition, the possible reaction to the strong van der Waals forces from hydrophobic residues is a moderate opening of the functional groups by 5° with maintained distance between carbon C-26 and C-27 due to additional twist in the absolute position of the C-25 carbon. These net effects show also small variation the LBP size, which is slightly confined in the presence of CF3 functional groups resulting in a tighter packing of the cavity (Figure 13B).

Nonsteroidal vitamin D mimics with phenylpyrrolyl pentane skeletons have been designed (159–165). (81,82) Among them, 159 shows clear antiproliferative effects on MCF-7 cells. In order to improve the biological activity of compound 159, derivatives were designed comprising side-chains terminated in a diethylcarbinol, hydrophilic groups or hydrophobic groups (160–165). The antiproliferative activities of the compounds were tested in MCF-7 cells, PC3 human prostate cancer cells, Caco2 human colon cancer cells, and HepG2 human liver cancer cells. Compound 160b exhibits the best antiproliferative activity, being more potent than the prototype compound 159 and 1,25(OH) 2 D 3 . Also the compounds 160a, 160c, 160d, 160f, 160g, 164b, and 165b show in all four model systems better antiproliferative activities than 159 and 1,25(OH) 2 D 3 . The R2 substitutions at the pyrrole-ring side-chains are crucial for the antiproliferative activity of the compounds. Molecules with hydrophilic groups at the end of the pyrrole-ring side-chain (160a, 160b, 160d, 160g, and 164b) are more potent than those bearing hydrophobic groups (161a, 161b, 162a–d, 163a, and 164b). Moreover, compounds 160a, 160c, 160d, 160g, and 164b were less cytotoxic than 159 and 1,25(OH) 2 D 3 . Compounds 160a–d, 164b, and 165b also display prodifferentiating activity. In reporter gene assays 164b is the most potent compound, whereas the transactivation potential of 160b and 160g is comparable to that of 1,25(OH) 2 D 3 .

A novel class of analogs, (83) where the C-ring and D-ring were replaced by an aromatic m-phenylene D-ring and an alkyl chain, were synthesized based on the formation of the triene system through a Pd-catalyzed ring-closure of an enol trifate and a subsequent Suzuki–Miyaura reaction with appropriate boronate in aqueous medium. (84) Compounds 166a–e efficiently induce the differentiation of human keratinocytes and show antiproliferative activity in MCF-7, PC-3, SKOV-3 (human ovary cancer), and HaCaT cells comparable to 1,25(OH) 2 D 3 . Compound 166a with the shortest chain at C-8 is most active not only in antiproliferative tests but also in reporter gene assays. Importantly, none of compounds 166a–e induce hypercalcemia. In a SCID mice xenograph model of aggressive MDA-MB-231 human breast cancer cells compound 166a shows high efficacy for tumor growth inhibition and overall survival.

Conclusions

This review demonstrated that clever and relevant chemistry significantly increased the number and variety of synthetic vitamin D analogs. Analog design had advanced and led to functional molecules, such as the o-carborane compounds, that are devoid of a 25-OH group. Moreover, there are now molecules that completely lack A- and/or CD-rings, such as p-carborane compounds, but still interact with VDR. Some of these nonsteroidal vitamin D analogs display high activity in vitro in combination with low calcemic effects in vivo. Thus, the area of nonsteroidal analogs and mimics is expected to further rise in future.

The assessment of the biological profile of VDR ligands is still primarily reduced to in vitro assays, such as VDR binding affinity, reporter gene assays, and antiproliferative and prodifferentiation measurements in different cancer cell lines. The variety in the assays makes a direct comparison of the different types of vitamin D analogs difficult. Moreover, a reliable extrapolation of the in vivo potential of the compounds is impossible without changing to a different set of assays, such as gene expression profiles in freshly isolated human peripheral blood mononuclear cells. (85)

Nowadays research on vitamin D analogs is nearly exclusively performed in academia and many interesting approaches for optimizing the profile of VDR ligands have not been explored to their limits. Accordingly, a complete picture is still missing and there is potential for improvements. The number of nearly 150 solved crystal structures of the VDR-LBD complexed with synthetic ligands is impressive and demonstrates the active interest of academia in understanding the molecular actions of VDR agonists and antagonists.

Unfortunately, failures of clinical trails focused on cancer have majorly dampened the interest of pharma industry in further developing vitamin D compounds. Since the natural hormone 1,25(OH) 2 D 3 primarily prevents bone- and immune-system-related diseases, the molecule and it synthetic derivatives may not be perfect drugs for the therapy of cancer. Nevertheless, calcipotriol-activated VDR in stroma of human pancreatic tumors had been shown to markedly reduce markers of inflammation and fibrosis in pancreatitis and human tumor stroma. (86) This suggests that vitamin D compounds rather affect immune cells of the microenvironment of tumors than directly inhibiting the proliferation of the cancer cells. In fact, to date, most genome-wide data on the action of VDR and its ligands are available from cells of the hematopoietic system. (87) This further emphasizes the impact of vitamin D and VDR for innate and adaptive immunity and suggests that these areas should be further explored for a commercial application. () () () () () () () () () () () () () () () () () () () () () () () () () () () () () () () () () () () () () () () () () () () () () () () () () () () () () () ()

Supporting Information

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.9b00208.

  • Table S1 describing all 143 publically available VDR ligand crystal structures with individual hyperlinks to the PDB and PubMed databases and citations of refs (90−144) (PDF)

  • jm9b00208_si_001.pdf (11.67 MB)

Terms & Conditions

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Author Information

    • Miguel A. Maestro - Departamento de Química-CICA, Universidade da Coruña, ES-15071 A Coruña, Spain

    • Ferdinand Molnár - School of Science and Technology, Department of Biology, Nazarbayev University, KZ-010000 Astana, Kazakhstan

  • The authors declare no competing financial interest.

Biographies

Miguel A. Maestro

Miguel A. Maestro received his Ph.D. in Chemistry from the University of Santiago de Compostela (Spain) in 1989. He did his postdoctoral stay in synthetic organic chemistry at the ETH-Zentrum (Zürich, Switzerland). In 1991 he joined the Faculty of Sciences at the University of A Coruña (Spain) studying synthetic methodologies towards vitamin D metabolites and analogs. Since 2018 he holds a Professor position at the Department of Chemistry. Prof. Maestro's interests are the synthesis of new vitamin D analogs with isotopic labeling and the atomic disposition of molecular structures through X-ray crystallography.

Ferdinand Molnár

Ferdinand Molnár received his Ph.D. in Biochemistry from the University of Kuopio (Kuopio, Finland) in 2006. He did his postdoctoral training in Structural Biology at the IGBMC (Illkirch, France). In 2008 he joined the School of Pharmacy at the University of Eastern Finland (Kuopio, Finland) studying nuclear receptor–ligand, −protein, and −DNA interactions. In 2018 he moved to the Nazarbayev University (Astana, Kazakhstan) where he holds an Associate Professor position at the Department of Biology. Prof. Molnár's interests are integrative structural biology and bioinformatics, eukaryotic transcriptional regulation in health and disease, and recombinant protein production.

Carsten Carlberg

Carsten Carlberg graduated in 1989 with a Ph.D. in Biochemistry at the Free University Berlin (Germany). After positions as postdoc at Roche (Basel, Switzerland), group leader at the University of Geneva (Switzerland), and docent at the University of Düsseldorf (Germany) he is since 2000 Full Professor of Biochemistry at the University of Eastern Finland in Kuopio (Finland). His work focuses on mechanisms of gene regulation by nuclear hormones, in particular on vitamin D. At present Prof. Carlberg has projects on epigenome-wide effects of vitamin D on the human immune system.

Acknowledgments

M.A.M. thanks Xunta de Galicia (Grant ED431B-2018/GI2105) for financial support. C.C. thanks the Academy of Finland for support.

Abbreviations Used
1,25(OH)2D3

1α,25-dihydroxyvitamin D3

1,25(OH)2D2

1α,25-dihydroxyvitamin D2

25(OH)D3

25-hydroxyvitamin D3

BGLAP

bone γ-carboxyglutamate protein (previously called osteocalcin)
CAMP

cathelicidin antimicrobial peptide
CYP24A1

cytochrome P450, family 24, subfamily A, polypeptide 1
DBP

vitamin D binding protein
IFNG

interferon-γ
LBD

ligand-binding domain
LBP

ligand-binding pocket
PDB

Protein Data Base
PTH

parathyroid hormone
RXR

retinoid X receptor
TNF

tumor necrosis factor
TSS

transcription start site
VDR

vitamin D receptor

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    American Journal of Clinical Nutrition (2008), 88 (2S), 491S-499SCODEN: AJCNAC; ISSN:0002-9165. (American Society for Nutrition)

    A review. New knowledge of the biol. and clin. importance of the steroid hormone 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] and its receptor, the vitamin D receptor (VDR), has made significant contributions to good bone health. Worldwide reports highlight a variety of vitamin D insufficiency and deficiency diseases. Despite many publications and scientific meetings reporting advances in vitamin D science, a disturbing realization is growing that the newer scientific and clin. knowledge is not translated into better human health. Over the past decades, the biol. sphere of influence of vitamin D3, as defined by the tissue distribution of the VDR, has broadened at least 9-fold from the target organs required for calcium homeostasis (intestine, bone, kidney, and parathyroid). The pluripotent steroid hormone 1α,25(OH)2D3 initiates the physiol. responses of ≥36 cell types that have VDR. In addn. to the kidney endocrine prodn. of circulating 1α,25(OH)2D3, a paracrine prodn. of this steroid hormone was found in ≥10 extrarenal organs. The fundamentals of the vitamin D endocrine system are described, including its potential contributions to good health in 5 physiol. arenas in which investigators have clearly documented new biol. actions of 1α,25(OH)2D3 through the VDR. The nutritional guidelines for vitamin D3 intake (defined by blood serum hydroxyvitamin D3 concns.) should be reevaluated with respect to contributions to good health that all 36 VDR target organs can provide.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtVSrsL3M&md5=4a4ea3a9d8433b8503c5c405109d6d3f

  4. 4

    Hollis, B. W. Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D. J. Nutr. 2005, 135 (2), 317– 322,  DOI: 10.1093/jn/135.2.317

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    Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D

    Hollis, Bruce W.

    Journal of Nutrition (2005), 135 (2), 317-322CODEN: JONUAI; ISSN:0022-3166. (American Society for Nutritional Sciences)

    A review. It has been more than 3 decades since the first assay assessing circulating 25-hydroxyvitamin D [25(OH)D] in human subjects was performed and led to the definition of "normal" nutritional vitamin D status, i.e., vitamin D sufficiency. Sampling human subjects, who appear to be free from disease, and assessing "normal" circulating 25(OH)D levels based on a Gaussian distribution of these values is now considered to be a grossly inaccurate method of identifying the normal range. Several factors contribute to the inaccuracy of this approach, including race, lifestyle habits, sunscreen usage, age, latitude, and inappropriately low dietary intake recommendations for vitamin D. The current adult recommendations for vitamin D, 200-600 IU/d, are very inadequate when one considers that a 10-15 min whole-body exposure to peak summer sun will generate and release up to 20,000 IU vitamin D-3 into the circulation. We are now able to better identify sufficient circulating 25(OH)D levels through the use of specific biomarkers that appropriately increase or decrease with changes in 25(OH)D levels; these include intact parathyroid hormone, calcium absorption, and bone mineral d. Using these functional indicators, several studies have more accurately defined vitamin D deficiency as circulating levels of 25(OH)D ≤ 80 nmol or 32 μg/L. Recent studies reveal that current dietary recommendations for adults are not sufficient to maintain circulating 25(OH)D levels at or above this level, esp. in pregnancy and lactation.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhsVKju74%253D&md5=5923029a9bf338feed0256c5c7764e99

  5. 5

    Carlberg, C. ; Polly, P. Gene regulation by vitamin D3 . Crit. Rev. Eukaryotic Gene Expression 1998, 8 (1), 19– 42,  DOI: 10.1615/CritRevEukarGeneExpr.v8.i1.20

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    5

    Gene regulation by vitamin D3

    Carlberg, Carsten; Polly, Patsie

    Critical Reviews in Eukaryotic Gene Expression (1998), 8 (1), 19-42CODEN: CRGEEJ; ISSN:1045-4403. (Begell House, Inc.)

    A review with ∼200 refs. The physiol. active form of vitamin D3, 1α,25-dihydroxyvitamin D3 (VD), is a nuclear hormone with pleiotropic action on the control of calcium homeostasis and bone formation, induction of cellular differentiation and apoptosis, inhibition of cellular proliferation, and other cellular signaling processes. The actions of the hormone are mediated by the vitamin D receptor (VDR), a transcription factor that is a nuclear receptor for VD and a member of the nuclear receptor superfamily. The structural relationship between the members of this transcription factor family suggests similar function in DNA binding, transactivation, and contact to other nuclear proteins. However, each nuclear receptor also demonstrates individual properties that are characteristic and not shared by its resp. relatives. In this review, both common as well as individual characteristics of VDR-mediated transcriptional regulation are critically discussed.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXltVSgtr4%253D&md5=26f8f8365a9dffce935e7795e942810f

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    Bouillon, R. ; Suda, T. Vitamin D: calcium and bone homeostasis during evolution. BoneKEy Rep. 2014, 3 , 480,  DOI: 10.1038/bonekey.2013.214

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    Vitamin D: calcium and bone homeostasis during evolution

    Bouillon Roger; Suda Tatsuo

    BoneKEy reports (2014), 3 (), 480 ISSN:2047-6396.

    Vitamin D3 is already found early in the evolution of life but essentially as inactive end products of the photochemical reaction of 7-dehydrocholestol with ultraviolet light B. A full vitamin D (refers to vitamin D2 and D3) endocrine system, characterized by a specific VDR (vitamin D receptor, member of the nuclear receptor family), specific vitamin D metabolizing CYP450 enzymes regulated by calciotropic hormones and a dedicated plasma transport-protein is only found in vertebrates. In the earliest vertebrates (lamprey), vitamin D metabolism and VDR may well have originated from a duplication of a common PRX/VDR ancestor gene as part of a xenobiotic detoxification pathway. The vitamin D endocrine system, however, subsequently became an important regulator of calcium supply for an extensive calcified skeleton. Vitamin D is essential for normal calcium and bone homeostasis as shown by rickets in vitamin D-deficient growing amphibians, reptiles, birds and mammals. From amphibians onward, bone is gradually more dynamic with regulated bone resorption, mainly by combined action of PTH and 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) on the generation and function of multinucleated osteoclasts. Therefore, bone functions as a large internal calcium reservoir, under the control of osteoclasts. Osteocytes also display a remarkable spectrum of activities, including mechanical sensing and regulating mineral homeostasis, but also have an important role in global nutritional and energy homeostasis. Mineralization from reptiles onward is under the control of well-regulated SIBLING proteins and associated enzymes, nearly all under the control of 1,25(OH)2D3. The vitamin D story thus started as inert molecule but gained an essential role for calcium and bone homeostasis in terrestrial animals to cope with the challenge of higher gravity and calcium-poor environment.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cflsFyjsA%253D%253D&md5=133665e3c491c7a90f588a120e23a88d

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    Hewison, M. An update on vitamin D and human immunity. Clin. Endocrinol. (Oxford, U. K.) 2012, 76 (3), 315– 325,  DOI: 10.1111/j.1365-2265.2011.04261.x

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    7

    An update on vitamin D and human immunity

    Hewison, Martin

    Clinical Endocrinology (Oxford, United Kingdom) (2012), 76 (3), 315-325CODEN: CLECAP; ISSN:0300-0664. (Wiley-Blackwell)

    A review. In the last 5 years, there has been a remarkable change in our understanding of the health benefits of vitamin D. The classical actions of vitamin D as a determinant of mineral metab. and rachitic bone disease have been expanded to include a broader role in skeletal homeostasis and prevalent bone disorders such as osteoporosis. However, it is the nonskeletal function of vitamin D that has attracted most attention. Although pluripotent responses to vitamin D have been recognized for many years, our new perspective on nonclassical vitamin D function stems from two more recent concepts. The first is that impaired, vitamin D status is common to many populations across the globe. This has prompted studies to explore the health impact of suboptimal circulating levels of vitamin D, with assocn. studies linking vitamin D "insufficiency" to several chronic health problems including autoimmune and cardiovascular disease, hypertension and common cancers. In support of a broader role for vitamin D in human health, studies in vitro and using animal models have highlighted immunomodulatory and anticancer effects of vitamin D that appear to depend on localized activation of vitamin D. The conclusion from these reports is that many nonclassical actions of vitamin D are independent of conventional vitamin D endocrinol. and are therefore more sensitive to variations in vitamin D status. The current review summarizes these developments, with specific ref. to the newly identified effects of vitamin D on the immune system, but also highlights the challenges in translating these observations to clin. practice.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XjvFOltr0%253D&md5=5de8d8657b19b6752a00a3c40d9d67d8

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    Rook, G. A. The role of vitamin D in tuberculosis. Am. Rev. Respir. Dis. 1988, 138 (4), 768– 770,  DOI: 10.1164/ajrccm/138.4.768

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    The role of vitamin D in tuberculosis

    Rook G A

    The American review of respiratory disease (1988), 138 (4), 768-70 ISSN:0003-0805.

    There is no expanded citation for this reference.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL1M%252FnsFehuw%253D%253D&md5=a028f2537d3cd794e3d656d991fafedf

  9. 9

    Ramagopalan, S. V. ; Maugeri, N. J. ; Handunnetthi, L. ; Lincoln, M. R. ; Orton, S. M. ; Dyment, D. A. ; Deluca, G. C. ; Herrera, B. M. ; Chao, M. J. ; Sadovnick, A. D. ; Ebers, G. C. ; Knight, J. C. Expression of the multiple sclerosis-associated MHC class II Allele HLA-DRB1*1501 is regulated by vitamin D. PLoS Genet. 2009, 5 (2), e1000369,  DOI: 10.1371/journal.pgen.1000369

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    Holick, M. F. ; Binkley, N. C. ; Bischoff-Ferrari, H. A. ; Gordon, C. M. ; Hanley, D. A. ; Heaney, R. P. ; Murad, M. H. ; Weaver, C. M. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 2011, 96 (7), 1911– 1930,  DOI: 10.1210/jc.2011-0385

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    Evaluation, treatment, and prevention of vitamin D deficiency: an endocrine society clinical practice guideline

    Holick, Michael F.; Binkley, Neil C.; Bischoff-Ferrari, Heike A.; Gordon, Catherine M.; Hanley, David A.; Heaney, Robert P.; Murad, M. Hassan; Weaver, Connie M.

    Journal of Clinical Endocrinology and Metabolism (2011), 96 (7), 1911-1930CODEN: JCEMAZ; ISSN:0021-972X. (Endocrine Society)

    A review. Objective: The objective was to provide guidelines to clinicians for the evaluation, treatment, and prevention of vitamin D deficiency with an emphasis on the care of patients who are at risk for deficiency. Participants: The Task Force was composed of a Chair, six addnl. experts, and a methodologist. The Task Force received no corporate funding or remuneration. Consensus Process: Consensus was guided by systematic reviews of evidence and discussions during several conference calls and e-mail communications. The draft prepd. by the Task Force was reviewed successively by The Endocrine Society's Clin. Guidelines Subcommittee, Clin. Affairs Core Committee, and cosponsoring assocns., and it was posted on The Endocrine Society web site for member review. At each stage of review, the Task Force received written comments and incorporated needed changes. Conclusions: Considering that vitamin D deficiency is very common in all age groups and that few foods contain vitamin D, the Task Force recommended supplementation at suggested daily intake and tolerable upper limit levels, depending on age and clin. circumstances. The Task Force also suggested the measurement of serum 25-hydroxyvitamin D level by a reliable assay as the initial diagnostic test in patients at risk for deficiency. Treatment with either vitamin D2 or vitamin D3 was recommended for deficient patients. At the present time, there is not sufficient evidence to recommend screening individuals who are not at risk for deficiency or to prescribe vitamin D to attain the noncalcemic benefit for cardiovascular protection.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXptlSku7o%253D&md5=cffb307dbc2a0dea8dd3a488d57b862a

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    Carlberg, C. The physiology of vitamin D-far more than calcium and bone. Front. Physiol. 2014, 5 , 335,  DOI: 10.3389/fphys.2014.00335

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    11

    The physiology of vitamin D-far more than calcium and bone

    Carlberg Carsten

    Frontiers in physiology (2014), 5 (), 335 ISSN:1664-042X.

    There is no expanded citation for this reference.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2M7itFyqtA%253D%253D&md5=ebe887960d12ce4e60ea2beb6ad1409f

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    Holick, M. F. Vitamin D deficiency. N. Engl. J. Med. 2007, 357 , 266– 281,  DOI: 10.1056/NEJMra070553

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    Vitamin D deficiency

    Holick, Michael F.

    New England Journal of Medicine (2007), 357 (3), 266-281CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)

    A review. The topics include dietary and other sources and metab. of vitamin D, vitamin D requirements, definition, causes and prevalence of vitamin D deficiency, deficiency treatment strategies, vitamin D roles in Ca and P metab. and bone metab., non-skeletal roles of vitamin D, relations to diseases (osteoporosis, bone fractures, cancer, diabetes mellitus, cardiovascular disease, etc.), and possible vitamin D intoxication.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXotVejsbc%253D&md5=5b0ca5fa97c3e39f946686a5f965a73d

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    Kupferschmidt, K. Uncertain verdict as vitamin D goes on trial. Science 2012, 337 (6101), 1476– 1478,  DOI: 10.1126/science.337.6101.1476

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    Uncertain verdict as vitamin D goes on trial

    Kupferschmidt Kai

    Science (New York, N.Y.) (2012), 337 (6101), 1476-8 ISSN:.

    There is no expanded citation for this reference.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38bovVKisg%253D%253D&md5=2ef6460bfbeceea37fc7de45cba84d28

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    Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D; Ross, A. C., Taylor, C. L., Yaktine, A. L., Del Valle, H. B. , Eds.; National Academies Press: Washington, DC, 2011.

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    Cheskis, B. J. ; Freedman, L. P. ; Nagpal, S. Vitamin D receptor ligands for osteoporosis. Curr. Opin Invest. Drugs 2006, 7 (10), 906– 911

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    Vitamin D receptor ligands for osteoporosis

    Cheskis, Boris J.; Freedman, Leonard P.; Nagpal, Sunil

    Current Opinion in Investigational Drugs (Thomson Scientific) (2006), 7 (10), 906-911CODEN: COIDAZ; ISSN:1472-4472. (Thomson Scientific)

    A review. 1α,25-Dihydroxyvitamin D3 (1,25-(OH)2D3), the biol. active metabolite of vitamin D, mediates its actions via the vitamin D receptor (VDR), a member of the superfamily of steroid/thyroid hormone/retinoid receptors. 1,25-(OH)2D3 is required for calcium and phosphorus homeostasis, and for normal skeletal development as well as maintenance of skeletal architecture. Two VDR ligands, calcitriol (1,25-(OH)2D3) and its synthetic analog alfacalcidol (1α-hydroxyvitamin D3), have been approved for the treatment of osteoporosis. However, the use of calcitriol and alfacalcidol is limited by their major side effect, hypercalcemia, which is mediated mainly by VDR activity in the small intestine. In order to identify VDR ligands with less hypercalcemia liability, a no. of pharmaceutical companies are pursuing efforts to develop synthetic vitamin D analogs. This review discusses the mechanism of action of vitamin D, and summarizes the currently approved anti-osteoporotic VDR agonists and compds. that are under development. The future directions of vitamin D research for the discovery of novel VDR agonists for osteoporosis are also discussed.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xht1eitbbK&md5=f7891754ec393b8f833cc57a15d9ae0a

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    Fogh, K. ; Kragballe, K. New vitamin D analogs in psoriasis. Curr. Drug Targets: Inflammation Allergy 2004, 3 (2), 199– 204,  DOI: 10.2174/1568010043343930

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    New vitamin D analogs in psoriasis

    Fogh, Karsten; Kragballe, Knud

    Current Drug Targets: Inflammation & Allergy (2004), 3 (2), 199-204CODEN: CDTICU; ISSN:1568-010X. (Bentham Science Publishers Ltd.)

    A review. Psoriasis is a common inflammatory and hyperproliferative skin disease characterized by infiltrated plaques of the skin and may involve nails, scalp and intertreginous areas. Recent years of research has shown that psoriasis can be treated topically with analogs of vitamin-D3. Impaired differentiation and increased proliferation of epidermal keratinocytes are key features in psoriatic lesions together with a local activation of T lymphocytes. Evidence has accumulated that analogs of vitamin D3 increase differentiation and inhibit proliferation of keratinocytes. Topical treatment with analogs of vitamin D3 have in a no. of trials shown improvement of psoriasis. Vitamin D analogs show the same efficacy as potent topical corticosteroids and do not produce skin atrophy during long-term therapy. Vitamin D analogs can be used both as monotherapy and in combination with topical corticosteroids, UVB, PUVA, acitretin, methotrexate and cyclosporine. The vitamin D3 analog calcipotriol was investigated in most detail and is available as an ointment, a cream and as a scalp soln. From clin. studies involving several thousands of patients, it can be concluded that calcipotriol is efficacious, safe and well-tolerated even on a long term basis.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXktlCkurc%253D&md5=574f592198a177dad0361f591ca3684c

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    Bouillon, R. ; Okamura, W. H. ; Norman, A. W. Structure-function relationships in the vitamin D endocrine system. Endocr. Rev. 1995, 16 , 200– 257,  DOI: 10.1210/edrv-16-2-200

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    Structure-function relationships in the vitamin D endocrine system

    Bouillon, Roger; Okamura, William H.; Norman, Anthony W.

    Endocrine Reviews (1995), 16 (2), 200-57CODEN: ERVIDP; ISSN:0163-769X.

    A review, with 578 refs., of the vitamin D endocrine system which discusses: the vitamin D endocrine system; vitamin D chem. and conformation; biol. activity of vitamin D; chem. synthesized analogs and biol. consequences; biol. and clin. implications; evaluation of structure-function studies - meta anal.; and future prospects.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXmtFWisrg%253D&md5=67e85ac98cda0c9ed87aafe1dcb7e322

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    Carlberg, C. ; Mouriño, A. New vitamin D receptor ligands. Expert Opin. Ther. Pat. 2003, 13 , 761– 772,  DOI: 10.1517/13543776.13.6.761

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    New vitamin D receptor ligands

    Carlberg, Carsten; Mourino, Antonio

    Expert Opinion on Therapeutic Patents (2003), 13 (6), 761-772CODEN: EOTPEG; ISSN:1354-3776. (Ashley Publications Ltd.)

    A review. More than 3000 synthetic analogs of the biol. active form of vitamin D, 1α,25-dihydroxyvitamin D3 (1α,25-(OH)2-D3), are presently known. All analogs interact with the mol. switch controlling nuclear 1α,25-(OH)2-D3 signaling, which is the complex of the vitamin D receptor (VDR), the retinoid X receptor (RXR) and a 1α,25-(OH)2-D3 response element (VDRE). The central element of this mol. switch is the ligand-binding domain (LBD) of the VDR, which can be stabilized by a 1α,25-(OH)2-D3 analog in either its agonistic or antagonistic conformation. In this article, the patent literature on 1α,25-(OH)2-D3 analogs described in the last 4 yr will be reviewed, and several new VDR ligands with promising selective profiles discussed. Although most of these ligands are agonists of the VDR, a few antagonists have been reported. Non-steroidal VDR ligands will be highlighted, as well as 1α,25-(OH)2-D3 analogs with two side chains.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXkt1yksbg%253D&md5=12aaf48a9323dc047bb5d65131bd39da

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    Carlberg, C. ; Molnár, F. ; Mouriño, A. Vitamin D receptor ligands: the impact of crystal structures. Expert Opin. Ther. Pat. 2012, 22 (4), 417– 435,  DOI: 10.1517/13543776.2012.673590

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    Vitamin D receptor ligands: the impact of crystal structures

    Carlberg, Carsten; Molnar, Ferdinand; Mourino, Antonio

    Expert Opinion on Therapeutic Patents (2012), 22 (4), 417-435CODEN: EOTPEG; ISSN:1354-3776. (Informa Healthcare)

    A review. Introduction: In the past years, the biol. active form of vitamin D3, 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), has received large appreciation due to the broad physiol. impact of the hormone and its nuclear receptor, the transcription factor vitamin D receptor (VDR). Recently, the understanding of VDR actions has progressed greatly, due to VDR crystal structures with various ligands. Areas covered: This review will present and discuss new synthetic agonistic and antagonistic 1α,25(OH)2D3 analogs in the context of the recent insights provided by VDR crystal structures. Expert opinion: During the last 5 years, a large no. of new 1α,25(OH)2D3 analogs, many of which have an interesting functional profile, have been patented. Moreover, for a surprisingly high no. of 1α,25(OH)2D3 analogs, the crystal structure data of their complex with the VDR is available. This structural information provides important insight into the functional potential of the VDR ligands and explains their agonistic and antagonistic action. However, so far, only for a few VDR ligands, a rational design, based on crystal structure information, has been applied. The design of future analogs may also take the specificity of co-factor interaction into account, in order to create selective VDR modulators.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XltVKis7g%253D&md5=93848114989527af5c7b2fc4475e538b

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    Evans, T. R. ; Colston, K. W. ; Lofts, F. J. ; Cunningham, D. ; Anthoney, D. A. ; Gogas, H. ; de Bono, J. S. ; Hamberg, K. J. ; Skov, T. ; Mansi, J. L. A phase II trial of the vitamin D analogue Seocalcitol (EB1089) in patients with inoperable pancreatic cancer. Br. J. Cancer 2002, 86 (5), 680– 685,  DOI: 10.1038/sj.bjc.6600162

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    20

    A phase II trial of the vitamin D analogue seocalcitol (EB1089) in patients with inoperable pancreatic cancer

    Evans, T. R. J.; Colston, K. W.; Lofts, F. J.; Cunningham, D.; Anthoney, D. A.; Gogas, H.; De Bono, J. S.; Hamberg, K. J.; Skov, T.; Mansi, J. L.

    British Journal of Cancer (2002), 86 (5), 680-685CODEN: BJCAAI; ISSN:0007-0920. (Nature Publishing Group)

    Inoperable cancer of the exocrine pancreas responds poorly to most conventional anti-cancer agents, and new agents are required to palliate this disease. Seocalcitol (EB1089), a vitamin D analog, can inhibit growth, induce differentiation and induce apoptosis of cancer cell lines in vitro and can also inhibit growth of pancreatic cancer xenografts in vivo. Thirty-six patients with advanced pancreatic cancer received once daily oral treatment with seocalcitol with dose escalation every 2 wk until hypercalcemia occurred, following which patients continued with maintenance therapy. The most frequent toxicity was the anticipated dose-dependent hypercalcemia, with most patients tolerating a dose of 10-15 μg per day in chronic administration. Fourteen patients completed at least 8 wk of treatment and were evaluable for efficacy, whereas 22 patients were withdrawn prior to completing 8 wk' treatment and in 20 of these patients withdrawal was due to clin. deterioration as a result of disease progression. No objective responses were obsd., with five of 14 patients having stable disease in whom the duration of stable disease was 82-532 days (median=168 days). The time to treatment failure (n=36) ranged from 22 to 847 days, and with a median survival of approx. 100 days. Seocalcitol is well tolerated in pancreatic cancer but has no objective anti-tumor activity in advanced disease. Further studies are necessary to det. if this agent has any cytostatic activity in this malignancy in minimal disease states.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XjtVKjsLY%253D&md5=53fcf1d69eee083a00f993a5a862268a

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    Heikkinen, S. ; Väisänen, S. ; Pehkonen, P. ; Seuter, S. ; Benes, V. ; Carlberg, C. Nuclear hormone 1α,25-dihydroxyvitamin D3 elicits a genome-wide shift in the locations of VDR chromatin occupancy. Nucleic Acids Res. 2011, 39 (21), 9181– 9193,  DOI: 10.1093/nar/gkr654

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    Nuclear hormone 1α,25-dihydroxyvitamin D3 elicits a genome-wide shift in the locations of VDR chromatin occupancy

    Heikkinen, Sami; Vaeisaenen, Sami; Pehkonen, Petri; Seuter, Sabine; Benes, Vladimir; Carlberg, Carsten

    Nucleic Acids Research (2011), 39 (21), 9181-9193CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)

    A global understanding of the actions of the nuclear hormone 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) and its vitamin D receptor (VDR) requires a genome-wide anal. of VDR binding sites. In THP-1 human monocytic leukemia cells we identified by ChIP-seq 2340 VDR binding locations, of which 1171 and 520 occurred uniquely with and without 1α,25(OH)2D3 treatment, resp., while 649 were common. De novo identified direct repeat spaced by 3 nucleotides (DR3)-type response elements (REs) were strongly assocd. with the ligand-responsiveness of VDR occupation. Only 20% of the VDR peaks diminishing most after ligand treatment have a DR3-type RE, in contrast to 90% for the most growing peaks. Ligand treatment revealed 638 1α,25(OH)2D3 target genes enriched in gene ontol. categories assocd. with immunity and signaling. From the 408 upregulated genes, 72% showed VDR binding within 400 kb of their transcription start sites (TSSs), while this applied only for 43% of the 230 downregulated genes. The VDR loci showed considerable variation in gene regulatory scenarios ranging from a single VDR location near the target gene TSS to very complex clusters of multiple VDR locations and target genes. In conclusion, ligand binding shifts the locations of VDR occupation to DR3-type REs that surround its target genes and occur in a large variety of regulatory constellations.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFCisb3O&md5=27300fb8c51aac888d1821e86804fd4b

  22. 22

    Gombart, A. F. ; Borregaard, N. ; Koeffler, H. P. Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3 . FASEB J. 2005, 19 (9), 1067– 1077,  DOI: 10.1096/fj.04-3284com

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    Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3

    Gombart, Adrian F.; Borregaard, Niels; Koeffler, H. Phillip

    FASEB Journal (2005), 19 (9), 1067-1077CODEN: FAJOEC; ISSN:0892-6638. (Federation of American Societies for Experimental Biology)

    The innate immune system of mammals provides a rapid response to repel assaults from numerous infectious agents including bacteria, viruses, fungi, and parasites. A major component of this system is a diverse combination of cationic antimicrobial peptides that include the α- and β-defensins and cathelicidins. In this study, we show that 1,25-dihydroxyvitamin D3 and three of its analogs induced expression of the human cathelicidin antimicrobial peptide (CAMP) gene. This induction was obsd. in acute myeloid leukemia (AML), immortalized keratinocyte, and colon cancer cell lines, as well as normal human bone marrow (BM)-derived macrophages and fresh BM cells from two normal individuals and one AML patient. The induction occurred via a consensus vitamin D response element (VDRE) in the CAMP promoter that was bound by the vitamin D receptor (VDR). Induction of CAMP in murine cells was not obsd. and expression of CAMP mRNA in murine VDR-deficient bone marrow was similar to wild-type levels. Comparison of mammalian genomes revealed evolutionary conservation of the VDRE in a short interspersed nuclear element or SINE in the CAMP promoter of primates that was absent in the mouse, rat, and canine genomes. Our findings reveal a novel activity of 1,25-dihydroxyvitamin D3 and the VDR in regulation of primate innate immunity.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXlvVCht78%253D&md5=425c818f65456ecd615991cdb53235b2

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    Haussler, M. R. ; Haussler, C. A. ; Jurutka, P. W. ; Thompson, P. D. ; Hsieh, J. C. ; Remus, L. S. ; Selznick, S. H. ; Whitfield, G. K. The vitamin D hormone and its nuclear receptor: molecular actions and disease states. J. Endocrinol. 1997, 154 (Suppl.), S57– S73

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    The vitamin D hormone and its nuclear receptor: molecular actions and disease states

    Haussler, M. R.; Haussler, C. A.; Jurutka, P. W.; Thompson, P. D.; Hsieh, J.-C.; Remus, L. S.; Selznick, S. H.; Whitfield, G. K.

    Journal of Endocrinology (1997), 154 (Suppl.), S57-S73CODEN: JOENAK; ISSN:0022-0795. (Journal of Endocrinology)

    A review, with 93 refs. Vitamin D plays a major role in bone mineral homeostasis by promoting the transport of calcium and phosphate to ensure that the blood levels of these ions are sufficient for the normal mineralization of type I collagen matrix in the skeleton. In contrast to classic vitamin D-deficiency rickets, a no. of vitamin D-resistant rachitic syndromes are caused by acquired and hereditary defects in the metabolic activation of the vitamin to its hormonal form, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), or in the subsequent functions of the hormone in target cells. The actions of 1,25(OH)2D3 are mediated by the nuclear vitamin D receptor (VDR), a phosphoprotein which binds the hormone with high affinity and regulates the expression of genes via zinc finger-mediated DNA binding and protein-protein interactions. In hereditary hypocalcemic vitamin D-resistant rickets (HVDRR), natural mutations in human VDR that confer patients with tissue insensitivity to 1,25(OH)2D3 are particularly instructive in revealing VDR structure/function relationships. These mutations fall into three categories: (i) DNA binding/nuclear localization, (ii) hormone binding and (iii) heterodimerization with retinoid X receptors (RXRs). That all three classes of VDR mutations generate the HVDRR phenotype is consistent with a basic model of the active receptor as a DNA-bound, 1,25(OH)2D3-liganded heterodimer of VDR and RXR. Vitamin D responsive elements (VDREs) consisting of direct hexanucleotide repeats with a spacer of three nucleotides have been identified in the promoter regions of pos. controlled genes expressed in bone, such as osteocalcin osteopontin, β3-integrin and vitamin D 24-OHase. The 1,25(OH)2D3 ligand promotes VDR-RXR heterodimerization and specific, high affinity VDRE binding, whereas the ligand for RXR, 9-cis retinoic acid (9-cis RA) is capable of suppressing 1,24(OH)2D3-stimulated transcription by diverting RXR to form homodimers. However, initial 1,25(OH)2D3 liganding of a VDR monomer renders it competent not only to recruit RXR into a heterodimer but also to conformationally silence the ability of its RR partner to bind 9-cis RA and dissoc. the heterodimer. Addnl. probing of protein-protein interactions has revealed that VDR also binds to basal transcription factor IIB (TFIIB) and, in the presence of 1,25(OH)2D3, an RXR-VDR-TFIIB ternary complex can be created in soln. Moreover, for transcriptional activation by 1,25(OH)2D3, both VDR and RXR require an intact short amphipathic α-helix, known as AF-2, positioned at their extreme C-termini. Because the AF-2 domains participate neither in VDR-RXR heterodimerization nor in TFIIB assocn., it is hypothesized that they contact, in a ligand-dependent fashion, transcriptional coactivators such as those of the steroid receptor coactivator family, constituting yet a third protein-protein interaction for VDR. Therefore, in VDR-mediated transcriptional activation, 1,25(OH)2D3 binding to VDR alters the conformation of the ligand binding domain such that it: (i) engages in strong heterodimerization with RXR to facilitate VDRE binding, (ii) influences the RXR ligand binding domain such that it is resistant to the binding of 9-cis RA but active in recruiting coactivator to its AF-2 and (iii) presents the AF-2 region in VDR for coactivator assocn. The above events, including bridging by coactivators to the TATA binding protein and assocd. factors, may position VDR such that it is able to attract TFIIB and the balance of the RNA polymerase II transcription machinery, culminating in repeated transcriptional initiation of VDRE-contg., vitamin D target genes. Such a model would explain the action of 1,25(OH)2D3 to elicit bone remodeling by stimulating osteoblast and osteoclast precursor gene expression, while concomitantly triggering the termination of its hormonal signal by including the 24-OHase catabolizing enzyme.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXlvVGgurw%253D&md5=215dcc04a6d0beb38acc1e9e7192953d

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    Carlberg, C. Vitamin D genomics: from in vitro to in vivo . Front. Endocrinol. 2018, 9 , 250,  DOI: 10.3389/fendo.2018.00250

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    Vitamin D Genomics: From In Vitro to In Vivo

    Carlberg Carsten

    Frontiers in endocrinology (2018), 9 (), 250 ISSN:1664-2392.

    The vitamin D3 metabolite 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] is the exclusive high-affinity ligand of the vitamin D receptor (VDR), a transcription factor with direct effects on gene expression. Transcriptome- and epigenome-wide data obtained in THP-1 human monocytes are the basis of the chromatin model of vitamin D signaling. The model describes, how VDR's spatio-temporal binding profile provides key insight into the pleiotropic action of vitamin D. The transcription of some 300 primary target genes is significantly modulated through the action of genomic VDR binding sites in concert with the pioneer transcription factor PU.1 and the chromatin organizer CTCF. In parallel, the short-term vitamin D intervention study VitDbol (NCT02063334) was designed, in order to extrapolate insight into vitamin D signaling from in vitro to in vivo. Before and 24 h after a vitamin D3 bolus chromatin and RNA were prepared from peripheral blood mononuclear cells for epigenome- and transcriptome-wide analysis. The study subjects showed a personalized response to vitamin D and could be distinguished into high, mid, and low responders. Comparable principles of vitamin D signaling were identified in vivo and in vitro concerning target gene responses as well as changes in chromatin accessibility. In conclusion, short-term vitamin D supplementation studies represent a new type of safe in vivo investigations demonstrating that vitamin D and its metabolites have direct effects on the human epigenome and modulate the response of the transcriptome in a personalized fashion.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1Mbks1Gltg%253D%253D&md5=f56ea8665b1aa3d77d3858dd0e700d99

  25. 25

    Verstuyf, A. ; Carmeliet, G. ; Bouillon, R. ; Mathieu, C. Vitamin D: a pleiotropic hormone. Kidney Int. 2010, 78 (2), 140– 145,  DOI: 10.1038/ki.2010.17

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    Vitamin D: a pleiotropic hormone

    Verstuyf, Annemieke; Carmeliet, Geert; Bouillon, Roger; Mathieu, Chantal

    Kidney International (2010), 78 (2), 140-145CODEN: KDYIA5; ISSN:0085-2538. (Nature Publishing Group)

    A review. The secosteroid hormone 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) is the natural ligand for the vitamin D receptor, a member of the nuclear receptor superfamily. Upon binding of the ligand, the vitamin D receptor heterodimerizes with the retinoid X receptor and binds to vitamin D response elements in the promoter region of target genes to induce/repress their expression. The target genes that have been identified so far are heterogeneous in nature and reflect the great spectrum of biol. activities of 1,25(OH)2D3. Within the last two decades, the receptor has been shown to be present not only in classical target tissues such as bone, kidney, and intestine, but also in many other nonclassical tissues, for example, in the immune system (T and B cells, macrophages, and monocytes), in the reproductive system (uterus, testis, ovary, prostate, placenta, and mammary glands), in the endocrine system (pancreas, pituitary, thyroid, and adrenal cortex), in muscles (skeletal, smooth, and heart muscles), and in brain, skin, and liver. Besides the almost universal presence of vitamin D receptors, different cell types (for example, keratinocytes, monocytes, bone, placenta) are capable of metabolizing 25-hydroxyvitamin D3 to 1,25(OH)2D3 by the enzyme 25(OH)D3-1α-hydroxylase, encoded by CYP27B1. The combined presence of CYP27B1 and the specific receptor in several tissues introduced the idea of a paracrine/autocrine role for 1,25(OH)2D3. Moreover, it has been demonstrated that 1,25(OH)2D3 can induce differentiation and inhibit proliferation of normal and malignant cells. Moreover, vitamin D deficiency is assocd. with an increased risk for nearly all major human diseases such as cancer, autoimmune diseases, cardiovascular, and metabolic diseases. In addn. to the treatment of bone disorders with 1,25(OH)2D3, these newly discovered functions open perspectives for the use of 1,25(OH)2D3 as an immune modulator (for example, for the treatment of autoimmune diseases or prevention of graft rejection), inhibitor of cell proliferation, and inducer of cell differentiation (cancer). Kidney International (2010) 78, 140-145; doi:10.1038/ki.2010.17; published online 24 Feb. 2010.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXotFejurY%253D&md5=42ce5515c9f85bbe759bdb021c2fd0ae

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    Wang, Y. ; Zhu, J. ; DeLuca, H. F. Where is the vitamin D receptor?. Arch. Biochem. Biophys. 2012, 523 (1), 123– 133,  DOI: 10.1016/j.abb.2012.04.001

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    Where is the vitamin D receptor?

    Wang, Yongji; Zhu, Jinge; DeLuca, Hector F.

    Archives of Biochemistry and Biophysics (2012), 523 (1), 123-133CODEN: ABBIA4; ISSN:0003-9861. (Elsevier B.V.)

    A review. The vitamin D receptor (VDR) is a member of the nuclear receptor superfamily and plays a central role in the biol. actions of vitamin D. VDR regulates the expression of numerous genes involved in calcium/phosphate homeostasis, cellular proliferation and differentiation, and immune response, largely in a ligand-dependent manner. To understand the global function of the vitamin D system in physiopathol. processes, great effort has been devoted to the detection of VDR in various tissues and cells, many of which have been identified as vitamin D targets. This review focuses on the tissue- and cell type-specific distribution of VDR throughout the body.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmtFans7k%253D&md5=a7ae32395484ed7553c2b5b63d1d9e28

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    Carlberg, C. ; Molnár, F. Vitamin D receptor signaling and its therapeutic implications: genome-wide and structural view. Can. J. Physiol. Pharmacol. 2015, 93 , 311– 318,  DOI: 10.1139/cjpp-2014-0383

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    Vitamin D receptor signaling and its therapeutic implications: Genome-wide and structural view1

    Carlberg, Carsten; Molnar, Ferdinand

    Canadian Journal of Physiology and Pharmacology (2015), 93 (5), 311-318CODEN: CJPPA3; ISSN:0008-4212. (Canadian Science Publishing)

    Vitamin D3 is one of the few natural compds. that has, via its metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) and the transcription factor vitamin D receptor (VDR), a direct effect on gene regulation. For efficiently applying the therapeutic and disease-preventing potential of 1,25(OH)2D3 and its synthetic analogs, the key steps in vitamin D signaling need to be understood. These are the different types of mol. interactions with the VDR, such as (i) the complex formation of VDR with genomic DNA, (ii) the interaction of VDR with its partner transcription factors, (iii) the binding of 1,25(OH)2D3 or its synthetic analogs within the ligand-binding pocket of the VDR, and (iv) the resulting conformational change on the surface of the VDR leading to a change of the protein-protein interaction profile of the receptor with other proteins. This review will present the latest genome-wide insight into vitamin D signaling, and will discuss its therapeutic implications.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXksVaitb0%253D&md5=49da36ecc688a7493fc593a4a311afd8

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    Rochel, N. ; Wurtz, J. M. ; Mitschler, A. ; Klaholz, B. ; Moras, D. Crystal structure of the nuclear receptor for vitamin D bound to its natural ligand. Mol. Cell 2000, 5 , 173– 179,  DOI: 10.1016/S1097-2765(00)80413-X

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    The crystal structure of the nuclear receptor for vitamin D bound to its natural ligand

    Rochel, N.; Wurtz, J. M.; Mitschler, A.; Klaholz, B.; Moras, D.

    Molecular Cell (2000), 5 (1), 173-179CODEN: MOCEFL; ISSN:1097-2765. (Cell Press)

    The action of 1α,25-dihydroxyvitamin D3 is mediated by its nuclear receptor (VDR), a ligand-dependent transcription regulator. The authors report the 1.8 Å resoln. crystal structure of the complex between a VDR ligand-binding domain (LBD) construct lacking the highly variable VDR-specific insertion domain and vitamin D. The construct exhibits the same binding affinity for vitamin D and transactivation ability as the wild-type protein, showing that the N-terminal part of the LBD is essential for its structural and functional integrity while the large insertion peptide is dispensable. The structure reveals the active conformation of the bound ligand and allows understanding of the different binding properties of some synthetic analogs.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXpvFKmsQ%253D%253D&md5=95e16d0014ab696065bcc1294cc271de

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    Molnár, F. Structural considerations of vitamin D signaling. Front. Physiol. 2014, 5 , 191,  DOI: 10.3389/fphys.2014.00191

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    29

    Structural considerations of vitamin D signaling

    Molnar Ferdinand

    Frontiers in physiology (2014), 5 (), 191 ISSN:1664-042X.

    Crystal structures represent the static picture in the life of a molecule giving a sneak preview what it might be in reality. Hence, it is very hard to extrapolate from these photos toward dynamic processes such as transcriptional regulation. Mechanistically VDR may be considered as molecular machine able to perform ligand-, DNA- and protein recognition, and interaction in a multi-task manner. Taking this into account the functional net effect will be the combination of all these processes. The long awaited answer to explain the differences in physiological effects for various ligands was one of the biggest disappointment that crystal structures provided since no substantial distinction could be made for the conformation of the active VDR-ligand complexes. This may have come from the limitation on the complexity of the available ligand-VDR structures. The recent studies with full length VDR-RXRα showed somewhat more comprehensive perspective for the 3D organization and possible function of the VDR-RXRα-cofactor complex. In addition to in vitro approaches, also computational tools had been introduced with the aim to get understanding on the mechanic and dynamic properties of the VDR complexes with some success. Using these methods and based on measurable descriptors such as pocket size and positions of side chains it is possible to note subtle differences between the structures. The meaning of these differences has not been fully understood yet but the possibility of a "butterfly effect" may have more extreme consequences in terms of VDR signaling. In this review, the three functional aspects (ligand-, DNA- and protein recognition, and binding) will be discussed with respect to available data as well as possible implication and questions that may be important to address in the future.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cflvF2ktQ%253D%253D&md5=21037ae95a70c9bb1d762dcc27d9cc30

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    Molnár, F. ; Peräkylä, M. ; Carlberg, C. Vitamin D receptor agonists specifically modulate the volume of the ligand-binding pocket. J. Biol. Chem. 2006, 281 (15), 10516– 10526,  DOI: 10.1074/jbc.M513609200

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    30

    Vitamin D Receptor Agonists Specifically Modulate the Volume of the Ligand-binding Pocket

    Molnar, Ferdinand; Peraekylae, Mikael; Carlberg, Carsten

    Journal of Biological Chemistry (2006), 281 (15), 10516-10526CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)

    Existing crystal structure data has indicated that 1α,25-dihydroxyvitamin D3 (1α,25(OH)2 D3) and its analogs bind the ligand-binding pocket (LBP) of the human vitamin D receptor in a very similar fashion. Because docking of a ligand into the LBP is a more flexible process than crystallog. can monitor, the authors analyzed 1α,25(OH)2D3, its 20-epi deriv. MC1288, the two side-chain analogs Gemini and Ro43-83582 (a hexafluoro-deriv.) by mol. dynamics simulations in a complex with the vitamin D receptor ligand-binding domain and a co-activator peptide. Superimposition of the structures showed that the side chain of MC1288, the first side chain of the conformation II of Gemini, the second side chain of Ro43-83582 in conformation I and the first side chain of Ro43-83582 in conformation II take the same agonistic position as the side chain of 1α,25(OH)2D3. Compared with the LBP of the natural hormone MC1288 reduced the vol. by 17%, and Gemini expanded it by 19%. The shrinking of the LBP of MC1288 and its expansion to accommodate the second side chain of Gemini or Ro43-83582 is the combined result of minor movements of more than 30 residues and major movements of a few crit. amino acids. The agonist-selective recognition of anchoring OH groups by the conformational flexible residues Ala 303, Leu 309, and His 397 was confirmed by in vitro assays. In summary, variations in the vol. of agonists lead to adaptations in the vol. of the LBP and alternative contacts of anchoring OH-groups.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xjt1Knsbw%253D&md5=f4dbef87347e1830e84bd4e76ca05463

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    Carlberg, C. Molecular basis of the selective activity of vitamin D analogues. J. Cell. Biochem. 2003, 88 (2), 274– 281,  DOI: 10.1002/jcb.10337

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    Molecular basis of the selective activity of vitamin D analogues

    Carlberg, Carsten

    Journal of Cellular Biochemistry (2003), 88 (2), 274-281CODEN: JCEBD5; ISSN:0730-2312. (Wiley-Liss, Inc.)

    A review. More than 2,000 synthetic analogs of the biol. active form of vitamin D, 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), are presently known. Basically, all of them interfere with the mol. switch of nuclear 1α,25(OH)2D3 signaling, which is the complex of the vitamin D receptor (VDR), the retinoid X receptor (RXR), and a 1α,25(OH)2D3 response element (VDRE). Central element of this mol. switch is the ligand-binding domain (LBD) of the VDR, which can be stabilized by a 1α,25(OH)2D3 analog either in its agonistic, antagonistic, or non-agonistic conformation. The positioning of helix 12 of the LBD is of most crit. importance for these conformations. In each of the three conformations, the VDR performs different protein-protein interactions, which then result in a characteristic functional profile. Most 1α,25(OH)2D3 analogs have been identified as agonists, a few are antagonists (e.g., ZK159222 and TEI-9647), and only Gemini and some of its derivs. act under restricted conditions as non-agonists. The functional profile of some 1α,25(OH)2D3 analogs, such as EB1089 and Gemini, can be modulated by protein and DNA interaction partners of the VDR. This provides them with some selectivity for DNA-dependent and -independent signaling pathways and VDRE structures.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXntlyluw%253D%253D&md5=634e39f155bc3297e43e4d316f95bfdf

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    Carlberg, C. Molecular endocrinology of vitamin D on the epigenome level. Mol. Cell. Endocrinol. 2017, 453 , 14– 21,  DOI: 10.1016/j.mce.2017.03.016

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    Molecular endocrinology of vitamin D on the epigenome level

    Carlberg, Carsten

    Molecular and Cellular Endocrinology (2017), 453 (), 14-21CODEN: MCEND6; ISSN:0303-7207. (Elsevier Ireland Ltd.)

    A review. The mol. endocrinol. of vitamin D is based on the facts that i) its metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) is the high affinity ligand of the nuclear receptor vitamin D receptor (VDR) and ii) the transcription factor VDR is the unique target of 1,25(OH)2D3 in the nucleus. Short-term alterations of the epigenome are primarily changes in the post-translational modification status of nucleosome-forming histone proteins, the consequences of which are i) a local increase or decrease in chromatin accessibility and ii) the activation or repression of gene transcription. Vitamin D has via VDR a direct effect on the expression of several hundred primary target genes implying numerous effects on the epigenome. Next-generation sequencing methods, such as ChIP-seq and FAIRE-seq, were applied to cellular model systems of vitamin D signaling, such as THP-1 human monocytes, and provided data for a chromatin model of vitamin D signaling. Key points of this model are that i) in the absence of ligand VDR binds to a limited no. of loci within accessible chromatin, ii) a stimulation with ligand increases the no. of DNA-bound VDR mols., iii) VDR's access to genomic DNA is supported by pioneer factors, such as PU.1 in monocytes, iv) VDR binding leads to local opening of chromatin and v) the binding strength of topol. assocg. domain anchor forming CCCTC-binding factor sites upstream and downstream of prominent VDR binding sites is changing in response to ligand stimulation. This model provides the present basis of the mol. endocrinol. of vitamin D and will be in future refined by the integration of vitamin D-sensitive chromatin markers and other genome-wide data, such as the 1,25(OH)2D3-sensitive binding of co-factors, chromatin modifying enzymes and chromatin remodeling proteins.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXks1GrsLk%253D&md5=f17a315c65b8fd47dddb95f66e047487

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    Wei, Z. ; Yoshihara, E. ; He, N. ; Hah, N. ; Fan, W. ; Pinto, A. F. M. ; Huddy, T. ; Wang, Y. ; Ross, B. ; Estepa, G. ; Dai, Y. ; Ding, N. ; Sherman, M. H. ; Fang, S. ; Zhao, X. ; Liddle, C. ; Atkins, A. R. ; Yu, R. T. ; Downes, M. ; Evans, R. M. Vitamin D switches BAF complexes to protect beta cells. Cell 2018, 173 (5), 1135– 1149,  DOI: 10.1016/j.cell.2018.04.013

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    Vitamin D switches BAF complexes to protect β Cells

    Wei, Zong; Yoshihara, Eiji; He, Nanhai; Hah, Nasun; Fan, Weiwei; Pinto, Antonio F. M.; Huddy, Timothy; Wang, Yuhao; Ross, Brittany; Estepa, Gabriela; Dai, Yang; Ding, Ning; Sherman, Mara H.; Fang, Sungsoon; Zhao, Xuan; Liddle, Christopher; Atkins, Annette R.; Yu, Ruth T.; Downes, Michael; Evans, Ronald M.

    Cell (Cambridge, MA, United States) (2018), 173 (5), 1135-1149.e15CODEN: CELLB5; ISSN:0092-8674. (Cell Press)

    A primary cause of disease progression in type 2 diabetes (T2D) is β cell dysfunction due to inflammatory stress and insulin resistance. However, preventing β cell exhaustion under diabetic conditions is a major therapeutic challenge. Here, we identify the vitamin D receptor (VDR) as a key modulator of inflammation and β cell survival. Alternative recognition of an acetylated lysine in VDR by bromodomain proteins BRD7 and BRD9 directs assocn. to PBAF and BAF chromatin remodeling complexes, resp. Mechanistically, ligand promotes VDR assocn. with PBAF to effect genome-wide changes in chromatin accessibility and enhancer landscape, resulting in an anti-inflammatory response. Importantly, pharmacol. inhibition of BRD9 promotes PBAF-VDR assocn. to restore β cell function and ameliorate hyperglycemia in murine T2D models. These studies reveal an unrecognized VDR-dependent transcriptional program underpinning β cell survival and identifies the VDR:PBAF/BAF assocn. as a potential therapeutic target for T2D.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXptlyrtLk%253D&md5=934b01629f4eb18ae6cbc3503fea3974

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    Carlberg, C. ; Campbell, M. J. Vitamin D receptor signaling mechanisms: Integrated actions of a well-defined transcription factor. Steroids 2013, 78 (2), 127– 136,  DOI: 10.1016/j.steroids.2012.10.019

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    Vitamin D receptor signaling mechanisms: Integrated actions of a well-defined transcription factor

    Carlberg, Carsten; Campbell, Moray J.

    Steroids (2013), 78 (2), 127-136CODEN: STEDAM; ISSN:0039-128X. (Elsevier)

    A review. The main physiol. actions of the biol. most active metabolite of vitamin D, 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), are calcium and phosphorus uptake and transport and thereby controlling bone formation. Other emergent areas of 1α,25(OH)2D3 action are in the control of immune functions, cellular growth and differentiation. All genomic actions of 1α,25(OH)2D3 are mediated by the transcription factor vitamin D receptor (VDR) that has been the subject of intense study since the 1980's. Thus, vitamin D signaling primarily implies the mol. actions of the VDR. In this review, we present different perspectives on the VDR that incorporate its role as transcription factor and member of the nuclear receptor superfamily, its dynamic changes in genome-wide locations and DNA binding modes, its interaction with chromatin components and its primary protein-coding and non-protein coding target genes and finally how these aspects are united in regulatory networks. By comparing the actions of the VDR, a relatively well-understood and characterized protein, with those of other transcription factors, we aim to build a realistic positioning of vitamin D signaling in the context of other intracellular signaling systems.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1yjsL0%253D&md5=5b804af56a0da0b98f6e78b14d04a1f3

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    Carlberg, C. ; Molnár, F. Current status of vitamin D signaling and its therapeutic applications. Curr. Top. Med. Chem. 2012, 12 (6), 528– 547,  DOI: 10.2174/156802612799436623

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    Current status of vitamin D signaling and its therapeutic applications

    Carlberg, Carsten; Molnar, Ferdinand

    Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2012), 12 (6), 528-547CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)

    A review. Vitamin D and in particular its biol. most active metabolite, 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), are central endocrine mols. that influence many aspects of human physiol., which are not only the well-known calcium and phosphorus up-take and transport controlling bone formation, but also the control of immune functions and of cellular growth and differentiation. Basically all actions of 1α,25(OH)2D3 are mediated by the transcription factor vitamin D receptor (VDR). The crystal structure of the VDR and detailed knowledge on its mol. interactions with the ligand provide significant insight into the mechanisms of vitamin D signaling. This applies also on the action of the huge no. of synthetic 1α,25(OH)2D3 analogs, which have been developed with the goal of a therapeutic application in hyper-proliferative diseases, such as psoriasis, benign prostate hyperplasia and different types of cancer, in immune functions, such as autoimmune diseases and microbial infections, or in bone disorders, such as osteoporosis. Moreover, detailed investigations on many VDR target genes and in particular the recently available genome-wide view on vitamin D signaling allows a more complete view on the potential of the nuclear hormone. In this review we discuss the latest insight into vitamin D signaling in context with the most prominent 1α,25(OH)2D3 analogs.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XkslWjsLs%253D&md5=4b0cd0599c397ddd9bce3f54404ab40a

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    Pérez-García, X. ; Rumbo, A. ; Larriba, M. J. ; Ordóñez, P. ; Muñoz, A. ; Mouriño, A. The first locked side-chain analogues of calcitriol (1α,25-dihydroxyvitamin D3) induce vitamin D receptor transcriptional activity. Org. Lett. 2003, 5 , 4033– 4036,  DOI: 10.1021/ol0351246

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    The First Locked Side-Chain Analogues of Calcitriol (1α,25-Dihydroxyvitamin D3) Induce Vitamin D Receptor Transcriptional Activity

    Perez-Garcia, Xenxo; Rumbo, Antonio; Larriba, Maria Jesus; Ordonez, Paloma; Munoz, Alberto; Mourino, Antonio

    Organic Letters (2003), 5 (22), 4033-4036CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)

    The synthesis of the first locked side-chain analogs of the natural hormone 1α,25-(OH)2-D3 and their effects on gene transcription in human colon cancer cells is described. I was more potent than 1α,25-(OH)2-D3 at inducing vitamin D receptor (VDR) transcriptional activity. Analogs II (R = m-OH, m-CMe2OH) show potency similar to that of 1α,25-(OH)2-D3, whereas II (R = p-CMe2OH) was less active. The novel analogs efficiently bind VDR in vivo to induce transcription from a consensus vitamin D responsive element (VDRE).

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXnvVegtb8%253D&md5=5e2bbf5e09cd0c89e48e2281bb0595b2

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    Sigueiro, R. ; Maestro, M. A. ; Mouriño, A. Synthesis of side-chain locked analogs of 1α,25-dhydroxyvitamin D3 bearing a C17 methyl group. Org. Lett. 2018, 20 (9), 2641– 2644,  DOI: 10.1021/acs.orglett.8b00849

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    Synthesis of Side-Chain Locked Analogs of 1α,25-Dihydroxyvitamin D3 Bearing a C17 Methyl Group

    Sigueiro, Rita; Maestro, Miguel A.; Mourino, Antonio

    Organic Letters (2018), 20 (9), 2641-2644CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)

    A convergent synthesis of side-chain locked vitamin D analogs I [R = Me, CF3], which bind strongly in silico to the vitamin D receptor (VDR), is described. The synthetic approach features an SN2'-syn displacement of carbamates by cuprates to set the challenging quaternary stereogenic center at C17 and a Pd-catalyzed construction of the triene system in the presence of a diyne moiety.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXnsVelu7s%253D&md5=f09779883a3635ddde52931b721ea7d2

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    Norman, A. W. ; Manchand, P. S. ; Uskokovic, M. R. ; Okamura, W. H. ; Takeuchi, J. A. ; Bishop, J. E. ; Hisatake, J.-I. ; Koeffler, H. P. ; Peleg, S. Characterization of a novel analog of 1α,25(OH)2-vitamin D3 with two side chains: interaction with its nuclear receptor and cellular actions. J. Med. Chem. 2000, 43 , 2719– 2730,  DOI: 10.1021/jm0000160

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    Characterization of a Novel Analogue of 1α,25(OH)2-Vitamin D3 with Two Side Chains: Interaction with Its Nuclear Receptor and Cellular Actions

    Norman, Anthony W.; Manchand, Percy S.; Uskokovic, Milan R.; Okamura, William H.; Takeuchi, Janet A.; Bishop, June E.; Hisatake, Jun-Iichi; Koeffler, H. Phillip; Peleg, Sara

    Journal of Medicinal Chemistry (2000), 43 (14), 2719-2730CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    The hormone 1α,25(OH)2-vitamin D3 (125D) binds to its nuclear receptor (VDR) to stimulate gene transcription activity. Inversion of configuration at C-20 of the side chain to generate 20-epi-1α,25(OH)2D3 (20E-125D) increases transcription 200-5000-fold over 125D with its 20-normal (20N) side chain. This enhancement has been attributed to the VDR ligand-binding domain (LBD) having different contact sites for 20N and 20E side chains that generate different VDR conformations. We synthesized 1α,25-dihydroxy-21-(3-hydroxy-3-methylbutyl)vitamin D3 (Gemini) (I) with two six-carbon side chains (both 20N and 20E orientations). Energy minimization calcns. indicate the Gemini side chain possesses significantly more energy min. than either 125D or 20E-125D (2346, 207, and 127 min., resp.). We compared activities of 125D, 20E-125D, and Gemini, resp., in several assays: binding to wild-type (100%, 147%, and 38%) and C-terminal-truncated mutant VDR; transcriptional activity (of the transfected osteopontin promoter in ROS 17/2.8 cells: ED50 10, 0.005, and 1.0 nM); mediation of conformational changes in VDR assessed by protease clipping (major trypsin-resistant fragment of 34, 34, and 28 kDa). For inhibition of cellular clonal growth of human leukemia (HL-60) and breast cancer (MCF7) cell lines, the ED50(125D)/ED50(Gem) was resp. 380 and 316. We conclude that while I readily binds to the VDR and generates unique conformational changes, none of them is able to permit a superior gene transcription activity despite the presence of a 20E side chain.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXktFSmu7g%253D&md5=138a35ae844e8022881469baf0709045

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    Herdick, M. ; Bury, Y. ; Quack, M. ; Uskokovic, M. R. ; Polly, P. ; Carlberg, C. Response element and coactivator-mediated conformational change of the vitamin D3 receptor permits sensitive interaction with agonists. Mol. Pharmacol. 2000, 57 (6), 1206– 1217

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    Response element and coactivator-mediated conformational change of the vitamin D3 receptor permits sensitive interaction with agonists

    Herdick, Michaela; Bury, Yvonne; Quack, Marcus; Uskokovic, Milan R.; Polly, Patsie; Carlberg, Carsten

    Molecular Pharmacology (2000), 57 (6), 1206-1217CODEN: MOPMA3; ISSN:0026-895X. (American Society for Pharmacology and Experimental Therapeutics)

    The vitamin D receptor (VDR) is the nuclear receptor for 1,25-dihydroxyvitamin D3 [1α,25(OH)2D3] that acts as a ligand-dependent transcription factor via combined contact with coactivator proteins (steroid receptor coactivator-1, transcriptional intermediary factor 2, and receptor assocd. coactivator 3) and specific DNA binding sites [vitamin D response elements (VDREs)]. Ligand-mediated conformational changes of the VDR contribute to the key mechanisms in this nuclear hormone signaling process. 1α,25(OH)2D3, MC1288 [20-epi-1α,25(OH)2D3], ZK161422 [20-methyl-1α,25(OH)2D3], and Ro27-2310 (also called Gemini, having two side chains at carbon 20) were used as model VDR agonists. The anal. of agonist-induced VDR conformations and coactivator interactions were found to be insufficient for extrapolating in vivo activities. In DNA-independent assays, such as classical limited protease digestions and glutathione S-transferase pull downs, Gemini seemed to be up to 10,000-fold and the other VDR agonists 10- to 100-fold weaker than in functional in vivo assays. A more accurate description of the gene regulatory potential of VDR agonists was obtained with all tested VDR agonists by analyzing VDR conformations in the context of VDRE-bound VDR-retinoid X receptor heterodimers, in such assays as gel supershift, gel shift clipping, and limited protease digestion in the presence of DNA and cofactor. Coactivators were found to shift the ligand sensitivity (by a factor of 4 for Gemini) and the ratio of VDR conformations in the presence of DNA toward the high-affinity ligand binding conformation (c1LPD). In conclusion, the induction of response element- and coactivator-modulated VDR conformations appears to be a key step for the gene regulatory function of a VDR agonist. The quantification of these effects would be of central importance for the evaluation of the cell-specific efficacy of systemically applied 1α,25(OH)2D3 analogs.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXjvVSjtrw%253D&md5=35dcd1d58e269a219e2b5abd8e73bceb

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    Väisänen, S. ; Peräkylä, M. ; Kärkkäinen, J. I. ; Uskokovic, M. R. ; Carlberg, C. Structural evaluation of the agonistic action of a vitamin D analog with two side chains binding to the nuclear vitamin D receptor. Mol. Pharmacol. 2003, 63 (6), 1230– 1237,  DOI: 10.1124/mol.63.6.1230

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    Structural evaluation of the agonistic action of a vitamin D analog with two side chains binding to the nuclear vitamin D receptor

    Vaisanen, Sami; Perakyla, Mikael; Karkkainen, Jouni I.; Uskokovic, Milan R.; Carlberg, Carsten

    Molecular Pharmacology (2003), 63 (6), 1230-1237CODEN: MOPMA3; ISSN:0026-895X. (American Society for Pharmacology and Experimental Therapeutics)

    The vitamin D receptor (VDR) is one of the endocrine members of the nuclear receptor superfamily and has a characteristic high affinity for its natural ligand 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3]. From a mechanistic point of view, the most interesting analog of 1α,25(OH)2D3 is the one that carries two side chains, referred to as Gemini. In this study, mol. dynamics (MD) simulations of the Gemini-VDR complex were performed that demonstrated that the binding of a ligand with a 25% increased vol. does not disturb the overall structure of the ligand-binding domain (LBD). It was found that one of the two side chains takes exactly the same position as the single side chain of the natural ligand, which suggests that the mol. mechanism of the agonism of Gemini is identical to that of 1α,25(OH)2D3. VDR single and double point mutants at L227, A303, I313, and L397 and in vitro and ex vivo assessment of their agonistic action confirmed the predictions of the MD simulations. Moreover, it was found that the second side chain of Gemini can choose between two binding positions within the ligand-binding pocket of the VDR. These two newly identified "corners" were characterized most specifically by the amino acids pairs L227/A303 and I313/L397. Therefore, Gemini is an important model compd. that allows further insight into the mol. actions of the VDR but is, in parallel, also a promising precursor for the design of even more potent 1α,25(OH)2D3 analogs.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXkt1Shu7o%253D&md5=14a7add926e6080269b0443d18cb5cef

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    Liu, Y. Y. ; Collins, E. D. ; Norman, A. W. ; Peleg, S. Differential interaction of 1α,25-dihydroxyvitamin D3 analogues and their 20-epi homologues with the vitamin D receptor. J. Biol. Chem. 1997, 272 (6), 3336– 3345,  DOI: 10.1074/jbc.272.6.3336

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    Differential interaction of 1α,25-dihydroxyvitamin D3 analogs and their 20-epi homologs with the vitamin D receptor

    Liu, Yan-Yun; Collins, Elaine D.; Norman, Anthony W.; Peleg, Sara

    Journal of Biological Chemistry (1997), 272 (6), 3336-3345CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)

    An important focus of structure-function studies of synthetic ligands for the vitamin D receptor (VDR) concerns the chiral center at carbon 20 of the steroid side chain; 20-epi analogs are 100-10,000 times more potent transcriptionally than the natural hormone 1α,25-dihydroxyvitamin D3 (1α(OH)2D3). The authors have compared the binding properties of three pairs of analogs either with a natural (N) or 20-epi (E) orientation. In intact cells, 45-60% of VDR·N-analog complexes, but only 5-20% of VDR·E-analog complexes, dissocd. over a 3-h interval. The two groups of ligands induced distinct changes in VDR conformation as revealed by protease clipping assays. Mapping of ligand-VDR binding activity by deletions indicated that amino acids 420-427 were important for high affinity of VDR·N-analog complexes, but not for VDR·E-analog complexes. Site-directed mutagenesis revealed that residues 421 and 422 were essential for 1α,25-(OH)2D3-induced conformational changes, high affinity of 1α,25-(OH)2D3 for VDR, and transcriptional activity, but not for binding of its 20-epi analog. In contrast, deletion of residues 396-427 abolished binding of 1α,25-(OH)2D3, but binding of its 20-epi analog was still detectable. The results suggest that the ligand-binding domain of VDR has multiple and different contact sites for the two families of side chain-modified ligands, resulting in VDR·ligand complexes with different half-lives and transcriptional activities.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXhtFelsr8%253D&md5=3979594507f22ad6f385e9e9e578f1c5

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    Maehr, H. ; Lee, H. J. ; Perry, B. ; Suh, N. ; Uskokovic, M. R. Calcitriol derivatives with two different side chains at C-20. V. Potent inhibitors of mammary carcinogenesis and inducers of leukemia differentiation. J. Med. Chem. 2009, 52 (17), 5505– 5519,  DOI: 10.1021/jm900780q

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    Calcitriol derivatives with two different side chains at C-20. V. Potent inhibitors of mammary carcinogenesis and inducers of leukemia differentiation

    Maehr, Hubert; Lee, Hong Jin; Perry, Bradford; Suh, Nanjoo; Uskokovic, Milan R.

    Journal of Medicinal Chemistry (2009), 52 (17), 5505-5519CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    Calcitriol analogs with two pendant tertiary alc. side chains I [R = (F3C)2C(OH); R1 = H, RXCH2; R2 = RXCH2, H; R3 = F, HO; X = RC≡C, (E)-RCH:CH, (Z)-RCH:CH; Y = CH2, C:CH2] are prepd. as antitumor agents and as inducers of differentiation; their structures are correlated to their antitumor and differentiation-inducing abilities. I (R3 = F) are the least active of the compds. tested; I [X = RC≡C, (E)-RCH:CH] are generally more active in inhibiting human breast cancer cell growth and at inducing differentiation in human leukemia cells than I [X = (Z)-RCH:CH]. Of the compds. prepd., I [R = (F3C)2C(OH); R1 = H, RXCH2; R2 = RXCH2, H; R3 = HO; X = RC≡C, (E)-RCH:CH; Y = CH2] are found to be most effective as as antitumor agents and as inducers of differentiation; I [R = (F3C)2C(OH); R1 = RXCH2; R2 = H; R3 = HO; X = RC≡C; Y = CH2] is selected as a lead compd. for further study. The structures of I [R = (F3C)2C(OH); R1 = RXCH2; R2 = H; R3 = HO; X = RC≡C; Y = CH2] and of one of the intermediates in the prepn. of the calcitriol analogs are detd. by X-ray crystallog.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtVSisL%252FE&md5=cce252b2098dd648e9193ea957715e1a

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    Okamoto, R. ; Gery, S. ; Kuwayama, Y. ; Borregaard, N. ; Ho, Q. ; Alvarez, R. ; Akagi, T. ; Liu, G. Y. ; Uskokovic, M. R. ; Koeffler, H. P. Novel Gemini vitamin D3 analogs: large structure/function analysis and ability to induce antimicrobial peptide. Int. J. Cancer 2014, 134 (1), 207– 217,  DOI: 10.1002/ijc.28328

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    Novel Gemini vitamin D3 analogs: large structure/function analysis and ability to induce antimicrobial peptide

    Okamoto Ryoko; Gery Sigal; Kuwayama Yoshio; Borregaard Niels; Ho Quoc; Alvarez Rocio; Akagi Tadayuki; Liu George Y; Uskokovic Milan R; Koeffler H Phillip

    International journal of cancer (2014), 134 (1), 207-17 ISSN:.

    We have synthesized 39 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] analogs having two side chains attached to carbon-20 (Gemini) with various modifications and compared their anticancer activities. Five structure-function rules emerged to identify analogs with enhanced anticancer activity. One of these active analogs, BXL-01-0126, was more potent than 1,25(OH)2D3 in mediating 50% clonal inhibition of cancer cell growth. Murine studies found that BXL-01-0126 and 1,25(OH)2D3 had nearly the same potency to raise serum calcium levels. Taken together, BXL-01-0126 when compared to 1,25(OH)2D3 has greater anticancer potency, but similar toxicity causing hypercalcemia. We focused on the effect of these compounds on the stimulation of expression of human cathelicidin antimicrobial peptide (CAMP) whose gene has a vitamin D response element in its promoter. Expression of CAMP mRNA and protein increased in a dose-response fashion after exposure of acute myeloid leukemia (AML) cells to the Gemini analog, BXL-01-126, in vitro. A xenograft model of AML was developed using U937 AML cells injected into NSG-immunodeficient mice. Administration of vitamin D3 compounds to these mice resulted in substantial levels of CAMP in the systemic circulation. This suggests a unique prophylactic treatment at diagnosis or during induction chemotherapy for AML patients to provide them with protection against various microbial infections through CAMP induction.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3sjjt1yksg%253D%253D&md5=3fcb330039e65bdc6f1b32f828540b6d

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    Otero, R. ; Seoane, S. ; Sigueiro, R. ; Belorusova, A. Y. ; Maestro, M. A. ; Perez-Fernandez, R. ; Rochel, N. ; Mouriño, A. Carborane-based design of a potent vitamin D receptor agonist. Chem. Sci. 2016, 7 , 1033– 1037,  DOI: 10.1039/C5SC03084F

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    Carborane-based design of a potent vitamin D receptor agonist

    Otero, Rocio; Seoane, Samuel; Sigueiro, Rita; Belorusova, Anna Y.; Maestro, Miguel A.; Perez-Fernandez, Roman; Rochel, Natacha; Mourino, Antonio

    Chemical Science (2016), 7 (2), 1033-1037CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)

    The vitamin D nuclear receptor (VDR) is a potential target for cancer therapy. It is expressed in many tumors and its ligand shows anticancer actions. To combine these properties with the application of boron neutron capture therapy (BNCT), we design and synthesize a potent VDR agonist based on the skeleton of the hormone 1α,25-dihydroxyvitamin D3 (1,25D) and an o-carborane (dicarba-o-closo-1,2-dodecaborane) at the end of its side chain. The present ligand is the first secosteroidal analog with the carborane unit that efficiently binds to VDR and functions as an agonist with 1,25D-like potency in transcriptional assay on vitamin D target genes. Moreover it exhibits similar antiproliferative and pro-differentiating activities but is significantly less hypercalcemic than 1,25D. The crystal structure of its complex with VDR ligand binding domain reveals its binding mechanism involving boron-mediated dihydrogen bonds that mimic vitamin D hydroxyl interactions. In addn. to the therapeutic interest, this study establishes the basis for the design of new unconventional vitamin D analogs contg. carborane moieties for specific mol. recognition, and drug research and development.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslWksbbL&md5=79f22baa2b453eddc7968d8fa467a806

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    Takahashi, E. ; Nakagawa, K. ; Suhara, Y. ; Kittaka, A. ; Nihei, K. ; Konno, K. ; Takayama, H. ; Ozono, K. ; Okano, T. Biological activities of 2α-substituted analogues of 1α,25-dihydroxyvitamin D3 in transcriptional regulation and human promyelocytic leukemia (HL-60) cell proliferation and differentiation. Biol. Pharm. Bull. 2006, 29 (11), 2246– 2250,  DOI: 10.1248/bpb.29.2246

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    Biological activities of 2α-substituted analogues of 1α,25-dihydroxyvitamin D3 in transcriptional regulation and human promyelocytic leukemia (HL-60) cell proliferation and differentiation

    Takahashi, Eiji; Nakagawa, Kimie; Suhara, Yoshitomo; Kittaka, Atsushi; Nihei, Ken-ichi; Konno, Katsuhiro; Takayama, Hiroaki; Ozono, Keiichi; Okano, Toshio

    Biological & Pharmaceutical Bulletin (2006), 29 (11), 2246-2250CODEN: BPBLEO; ISSN:0918-6158. (Pharmaceutical Society of Japan)

    Biol. activities of 2α-substituted 1α,25-dihydroxyvitamin D3 analogs were evaluated in vitro. Their binding affinity was examd. with calf thymus cytosolic vitamin D receptor (VDR) and rat plasma vitamin D-binding protein (DBP). In addn., the transcriptional activity of the analogs was measured using a rat 25-hydroxyvitamin D3-24-hydroxylase gene promoter, a human osteocalcin gene promoter, and VDR-GAL4 system. This study investigated the biol. activities of 2α-substituted analogs in comparison with 2β-substituted analogs at the mol. level, with regard to the structural differences of alkyl, hydroxyalkyl, hydroxyalkoxy substituents at the 2-position of 1α,25-dihydroxyvitamin D3.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXms1ChsA%253D%253D&md5=5df9cab45d14c325f733c119480f59cf

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    Honzawa, S. ; Takahashi, N. ; Yamashita, A. ; Sugiura, T. ; Kurihara, M. ; Arai, M. A. ; Kato, S. ; Kittaka, A. Synthesis of a 1α-C-methyl analogue of 25-hydroxyvitamin D3: interaction with a mutant vitamin D receptor Arg274Leu. Tetrahedron 2009, 65 (34), 7135– 7145,  DOI: 10.1016/j.tet.2009.06.029

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    Synthesis of a 1α-C-methyl analogue of 25-hydroxyvitamin D3: Interaction with a mutant vitamin D receptor Arg274Leu

    Honzawa, Shinobu; Takahashi, Naoyuki; Yamashita, Atsushi; Sugiura, Takayuki; Kurihara, Masaaki; Arai, Midori A.; Kato, Shigeaki; Kittaka, Atsushi

    Tetrahedron (2009), 65 (34), 7135-7145CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)

    Vitamin D3 analogs have been developed for a mutant vitamin D receptor (VDR), Arg274Leu. The mutant VDR has a mutation at Arg274, which forms an important hydrogen bond with 1α-OH of 1α,25-dihydroxyvitamin D3 (I) to anchor the ligand tightly in the VDR ligand binding pocket. Stereoselective synthesis of the A-ring part of the novel vitamin D analog, 2α-(3-hydroxypropyl)-1α-methyl-25-hydroxyvitamin D3 (II), from D-galactose was accomplished with the key steps of the introduction of the Me and allyl groups to the chiral building blocks. The new analog II is ca. 7.3-fold more active than the natural hormone I.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXptVGgtLg%253D&md5=73d946aa5fa3598b811e7d47695dfecb

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    Sawada, D. ; Tsukuda, Y. ; Yasuda, K. ; Sakaki, T. ; Saito, H. ; Takagi, K. ; Takenouchi, K. ; Chen, T. C. ; Reddy, G. S. ; Kittaka, A. Synthesis and biological activities of 1α,4α,25- and 1α,4β,25-trihydroxyvitamin D3 and their metabolism by human CYP24A1 and UDP-glucuronosyltransferase. Chem. Pharm. Bull. 2012, 60 (10), 1343– 1346,  DOI: 10.1248/cpb.c12-00526

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    Synthesis and biological activities of 1α,4α,25- and 1α,4β,25-trihydroxyvitamin D3 and their metabolism by human CYP24A1 and UDP-glucuronosyltransferase

    Sawada, Daisuke; Tsukuda, Yuya; Yasuda, Kaori; Sakaki, Toshiyuki; Saito, Hiroshi; Takagi, Ken-ichiro; Takenouchi, Kazuya; Chen, Tai C.; Reddy, G. Satyanarayana; Kittaka, Atsushi

    Chemical & Pharmaceutical Bulletin (2012), 60 (10), 1343-1346CODEN: CPBTAL; ISSN:0009-2363. (Pharmaceutical Society of Japan)

    A previous report has demonstrated the existence of a C4-hydroxylated vitamin D2 metabolite in serum of rats treated with pharmacol. doses of vitamin D2. However, the biol. significance and metabolic fate of this metabolite have not been described. To explore its potential biol. activity, the authors prepd. 1α,4α,25-trihydroxyvitamin D3 and its diastereoisomer, 1α,4β,25-trihydroxyvitamin D3 by a Trost coupling reaction (Tsuji-Trost reaction) and studied their vitamin D receptor (VDR) binding affinity, osteocalcin promoter transactivation activity and their further metab. by human CYP24A1 as well as by human liver microsomal fraction based on CYP-glucuronosyltransferase and UDP-glucuronosyltransferase (UGTs)-reactions. The title compds. thus formed included (1R,2S,4S,6E)-5-methylene-6-[(2E)-2-[(1R,3aS,7aR)-octahydro-1-[(1R)-5-hydroxy-1,5-dimethylhexyl]-7a-methyl-4H-inden-4-ylidene]ethylidene]-1,2,4-cyclohexanetriol (I) [i.e., 1α,4β,25-trihydroxyvitamin D3] and 1α,4α,25-trihydroxyvitamin D3. The synthesis of the target compds. was achieved using (2S,4S)-4-(benzoyloxy)-2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-5-hexenal as a starting material.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVCgtbbK&md5=0ed04ef2cfb1acfc2a112119131008dc

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    Sibilska, I. K. ; Szybinski, M. ; Sicinski, R. R. ; Plum, L. A. ; Deluca, H. F. Highly potent 2-methylene analogs of 1α,25-dihydroxyvitamin D3: synthesis and biological evaluation. J. Steroid Biochem. Mol. Biol. 2013, 136 , 9– 13,  DOI: 10.1016/j.jsbmb.2013.02.001

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    48

    Highly potent 2-methylene analogs of 1α,25-dihydroxyvitamin D3: Synthesis and biological evaluation

    Sibilska, Izabela K.; Szybinski, Marcin; Sicinski, Rafal R.; Plum, Lori A.; DeLuca, Hector F.

    Journal of Steroid Biochemistry and Molecular Biology (2013), 136 (), 9-13CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier Ltd.)

    As a continuation of studies on a structure-activity relationship of vitamin D compds. the authors have synthesized new calcitriol analogs characterized by the presence of an exo-methylene substituent at C-2. The A-ring dienyne synthon was prepd. from com. available quinic acid by two different synthetic routes and it was then coupled with a triflate enol derived from the corresponding (20R)-Grundman ketone or (20S)-Grundman ketone by a palladium catalyzed Sonogashira reaction. The obtained 1α,25-dihydroxy-2-methylene-vitamin D3 analogs, epimeric at C-20, were biol. evaluated by in vitro and in vivo studies at the vitamin D receptor (VDR). Both isomers exhibited unique activity profiles and greater biol. potency than 1α,25-(OH)2D3. It was established that the biol. profiles of the newly obtained vitamin D compds. depend on the configuration at C-20. Thus, introduction of 2-methylene substituent to the calcitriol mol. together with alteration of stereochem. of its side chain induces remarkable changes in a VDR-mediated signaling response and enhances biol. activity. The title compds. thus formed included a vitamin D analog (20R)-epimer (I) [(1R,3R,5Z)-2,4-bis(methylene)-5-[(2E)-2-[(1R,3aS,7aR)-octahydro-1-[(1R)-5-hydroxy-1,5-dimethylhexyl]-7a-methyl-4H-inden-4-ylidene]ethylidene]-1,3-cyclohexanediol] and its (20S)-epimer. I is an analog of (1R,3S,5Z)-4-methylene-5-[(2E)-2-[(1R,3aS,7aR)-octahydro-1-[(1R)-5-hydroxy-1,5-dimethylhexyl]-7a-methyl-4H-inden-4-ylidene]ethylidene]-1,3-cyclohexanediol (calcitriol, 1α,25-dihydroxyvitamin D3, 1,25-dihydroxycholecalciferol). The synthesis of the target compds. was achieved using (1R,3R,5R)-1-(acetyloxy)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-6-oxabicyclo[3.2.1]octane-4,7-dione, 1,1,1-trifluoromethanesulfonic acid (1R,3aR,7aR)-1-[(1R)-1,5-dimethyl-5-[(triethylsilyl)oxy]hexyl]-2,3,3a,6,7,7a-hexahydro-7a-methyl-1H-inden-4-yl ester and its epimer as starting materials. This article is part of a Special Issue entitled Vitamin D Workshop.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjtl2isL4%253D&md5=d8a603b3f08e012398b0475845a4825d

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    Piotrowska, A. ; Wierzbicka, J. ; Nadkarni, S. ; Brown, G. ; Kutner, A. ; Zmijewski, M. A. Antiproliferative activity of double point modified analogs of 1,25-dihydroxyvitamin D2 against human malignant melanoma cell lines. Int. J. Mol. Sci. 2016, 17 (1), E76,  DOI: 10.3390/ijms17010076

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    49

    Antiproliferative activity of double point modified analogs of 1,25-dihydroxyvitamin D2 against human malignant melanoma cell lines

    Piotrowska, Anna; Wierzbicka, Justyna; Nadkarni, Sharmin; Brown, Geoffrey; Kutner, Andrzej; Zmijewski, Michal A.

    International Journal of Molecular Sciences (2016), 17 (1), 76/1-76/16CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)

    Vitamin D is a lipid sol. steroid hormone with pleiotropic biol. properties, including regulation of cell proliferation, differentiation and apoptosis. As to these desirable anticancer actions, 1,25-dihydroxyvitamins D and analogs have been reported to inhibit the proliferation and to induce differentiation of a wide variety of cancer cell types, including human malignant melanoma. However, there is a need for novel and more efficacious vitamin D analogs, and how best to design such is still an open issue. A series of double point modified (DPM) analogs of 1,25-dihydroxyvitamin D2 (1,25(OH)2D3) induced differentiation of the vitamin D receptor (VDR) pos. A375 and VDR neg. SK-MEL 188b human malignant melanoma cell lines. Surprisingly, the dose of 1,25(OH)2D3 required to inhibit the proliferation of the A375 melanoma cell line by was several fold lower than that required in the case of 1,25(OH)2D3. To evaluate the impact of the modification in the side chain (addnl. 22-hydroxyl) and in the A-ring (5,6-trans modification), the regular side-chain of vitamin D2 or D3 was retained in the structure of our analogs. As expected, 5,6-trans modification was advantageous to enhancing the anti-proliferative activity of analogs, but not as a single point modification (SPM). Very unexpectedly, the addnl. 22-hydroxyl in the side-chain reduced significantly the anti-proliferative activity of both the natural and 5,6-trans series analogs. Finally, an induction of pigmentation in melanoma SK-MEL 188b cells was obsd. to sensitized cells to the effect of vitamin D analogs.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXktFOqtw%253D%253D&md5=170c36c2614f03dd3b48554fb3bc268a

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    Corcoran, A. ; Nadkarni, S. ; Yasuda, K. ; Sakaki, T. ; Brown, G. ; Kutner, A. ; Marcinkowska, E. Biological evaluation of double point modified analogues of 1,25-dihydroxyvitamin D2 as potential anti-leukemic agents. Int. J. Mol. Sci. 2016, 17 (2), E91,  DOI: 10.3390/ijms17020091

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    50

    Biological evaluation of double point modified analogues of 1,25-dihydroxyvitamin D2 as potential anti-leukemic agents

    Corcoran, Aoife; Nadkarni, Sharmin; Yasuda, Kaori; Sakaki, Toshiyuki; Brown, Geoffrey; Kutner, Andrzej; Marcinkowska, Ewa

    International Journal of Molecular Sciences (2016), 17 (2), 91/1-91/10CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)

    Structurally similar double-point modified analogs of 1,25-dihydroxyvitamin D2 (1,25D2) were screened in vitro for their pro-differentiating activity against the promyeloid cell line HL60. Their affinities towards human full length vitamin D receptor (VDR) and metabolic stability against human vitamin D 24-hydroxylase (CYP24A1) were also tested. The analogs (PRI-1730, PRI-1731, PRI-1732, PRI-1733 and PRI-1734) contained 5,6-trans modification of the A-ring and of the triene system, addnl. hydroxyl or unsatn. at C-22 in the side chain and reversed abs. configuration (24-epi) at C-24 of 1,25D2. As presented in this paper, introduction of selected structural modifications simultaneously in two distinct parts of the vitamin D mol. resulted in a divergent group of analogs. Analogs showed lower VDR affinity in comparison to that of the parent hormones, 1,25D2 and 1,25D3, and they caused effective HL60 cell differentiation only at high concns. of 100 nM and above. Unexpectedly, introducing of a 5,6-trans modification combined with C-22 hydroxyl and 24-epi configuration switched off entirely the cell differentiation activity of the analog (PRI-1734). However, this analog remained a moderate substrate for CYP24A1, as it was metabolized at 22%, compared to 35% for 1,25D2. Other analogs from this series were either less (12% for PRI-1731 and PRI-1733) or more (52% for PRI-1732) resistant to the enzymic deactivation. Although the inactive analog PRI-1734 failed to show VDR antagonism, when tested in HL60 cells, its structure might be a good starting point for our design of a vitamin D antagonist.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitFShsLfO&md5=1c19bedb651c37feb29ac81bf002abcf

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    Saito, N. ; Kittaka, A. Highly potent vitamin D receptor antagonists: design, synthesis, and biological evaluation. ChemBioChem 2006, 7 (10), 1478– 1490,  DOI: 10.1002/cbic.200600054

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    Highly potent vitamin D receptor antagonists: design, synthesis, and biological evaluation

    Saito, Nozomi; Kittaka, Atsushi

    ChemBioChem (2006), 7 (10), 1478-1490CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)

    A review. Vitamin D receptor (VDR) antagonists have attracted significant levels of interest because of their potential utility in the treatment of Paget's disease, which is known as the most flagrant example of disordered bone remodeling and the second most common bone disease after osteoporosis in Anglo-Saxons. Recent studies on Paget's disease suggested a specific increase in osteoclasts' sensitivity to the differentiation activity of active vitamin D3 as the principal mechanism for abnormal bone formation. We set out to conduct a structure-activity relationship study on the first VDR antagonists, TEI-9647 and TEI-9648 (25-dehydro-1α-hydroxyvitamin D3-26,23-lactone), with the goal of improved VDR antagonistic activity. Given that both potent agonists and antagonists must have high affinity for the VDR, we hoped that our accumulated knowledge in the field of VDR agonists would help us identify potent antagonists. First 2α-modified TEI-9647 analogs were synthesized, and then 24-substitution to stabilize the lactone structure under physiol. conditions was investigated. Finally, 2α-modified 24-methyl-, 24,24-dimethyl-, and 24,24-ethano-25-dehydro-1α-hydroxyvitamin D3-26,23-lactone analogs were synthesized. The synthesis of the 24,24-ethano-TEI lactone was accomplished through Ru-catalyzed intermol. enyne metathesis of the alky-none CD-ring side chain with ethylene to give a dienone, followed by regioselective cyclopropanation. It was found that 2α,24,24-trimethyl-TEI-9647 (39) possessed an antagonistic activity (IC50 = 0.093 nM) approx. 90 times that of the original TEI-9647 (IC50 = 8.3 nM).

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtFemsr3J&md5=76af443b9b7034f8efa128a0841db712

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    Saito, N. ; Matsunaga, T. ; Saito, H. ; Anzai, M. ; Takenouchi, K. ; Miura, D. ; Namekawa, J. ; Ishizuka, S. ; Kittaka, A. Further synthetic and biological studies on vitamin D hormone antagonists based on C24-alkylation and C2α-functionalization of 25-dehydro-1α-hydroxyvitamin D3-26,23-lactones. J. Med. Chem. 2006, 49 (24), 7063– 7075,  DOI: 10.1021/jm060797q

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    52

    Further Synthetic and Biological Studies on Vitamin D Hormone Antagonists Based on C24-Alkylation and C2α-Functionalization of 25-Dehydro-1α-hydroxyvitamin D3-26,23-lactones

    Saito, Nozomi; Matsunaga, Toshihiro; Saito, Hiroshi; Anzai, Miyuki; Takenouchi, Kazuya; Miura, Daishiro; Namekawa, Jun-ichi; Ishizuka, Seiichi; Kittaka, Atsushi

    Journal of Medicinal Chemistry (2006), 49 (24), 7063-7075CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    An efficient synthesis and the biol. evaluation of 80 novel analogs of 25-dehydro-1α-hydroxyvitamin D3-26,23S-lactone I (TEI-9647) and its 23R epimer in which the lactone ring was systematically functionalized by introduction of a C1 to C4 primary alkyl group at the C24 position (5 sets of 4 diastereomers), together with their C2α-Me, 3-hydroxypropyl, and 3-hydroxypropoxy-substituted derivs. were described. The triene structure of the vitamin D3 was constructed using palladium-catalyzed alkenylative cyclization of the A-ring precursor enyne with the CD-ring counterpart bromoolefin having the C24-alkylated lactone moiety on the side chain. The CD-ring precursors having 23,24-cis lactones were prepd. by using a chromium-mediated syn-selective allylation-lactonization process, and the 23,24-trans lactone derivs. were derived from these via inversion of the C23 stereochem. The biol. evaluation revealed that both binding affinity for chick vitamin D hormone receptor and antagonistic activity (inhibition of vitamin D hormone induced HL-60 cell differentiation) were affected by the orientation and chain-length of the primary alkyl group on the lactone ring. Furthermore, the C2α-functionalization of the C24-alkylated vitamin D3 lactones dramatically enhanced their biol. activities. The most potent compd. to emerge, (23S,24S)-2α-(3-hydroxypropoxy)-24-Pr exhibited almost 1000-fold stronger antagonistic activity (IC50 = 7.4 pM) than I (IC50 = 6.3 nM).

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    Sakamaki, Y. ; Inaba, Y. ; Yoshimoto, N. ; Yamamoto, K. Potent antagonist for the vitamin D receptor: vitamin D analogues with simple side chain structure. J. Med. Chem. 2010, 53 (15), 5813– 5826,  DOI: 10.1021/jm100649d

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    53

    Potent Antagonist for the Vitamin D Receptor: Vitamin D Analogues with Simple Side Chain Structure

    Sakamaki, Yuta; Inaba, Yuka; Yoshimoto, Nobuko; Yamamoto, Keiko

    Journal of Medicinal Chemistry (2010), 53 (15), 5813-5826CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    We previously reported that 22S-butyl-25,26,27-trinor-1α,24-dihydroxyvitamin D32 was a potent VDR antagonist. The X-ray crystal structure of the ligand binding domain of VDR complexed with 2 indicated that this ligand induces an extra cavity within the ligand-binding pocket. The structure also showed that the ligand forms only poor hydrophobic interactions with helix 12 of the protein. Here, to study the effects of the induction of the extra cavity and of insufficient interactions with helix 12 on antagonism, we designed and synthesized a series of vitamin D3 analogs with or without a 22-alkyl substituent and evaluated their biol. potency. We found that the two 22-Bu analogs act as full antagonists, the 22-Et analogs and 22-Bu analog act as partial agonists, and the others act as full agonists for VDR. It is intriguing that I is a potent agonist for VDR, whereas its 26,27-dinor analog is a potent antagonist. Analog I recruited coactivator SRC-1 well, but analog did not. These results indicate that a combination of induction of the extra cavity and insufficient hydrophobic interactions with helix 12 is important for VDR antagonism in this class of ligands.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXosVGhsb0%253D&md5=708c2f982322f8e0409b9ee163dab7dd

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    Yoshimoto, N. ; Sakamaki, Y. ; Haeta, M. ; Kato, A. ; Inaba, Y. ; Itoh, T. ; Nakabayashi, M. ; Ito, N. ; Yamamoto, K. Butyl pocket formation in the vitamin D receptor strongly affects the agonistic or antagonistic behavior of ligands. J. Med. Chem. 2012, 55 (9), 4373– 4381,  DOI: 10.1021/jm300230a

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    54

    Butyl Pocket Formation in the Vitamin D Receptor Strongly Affects the Agonistic or Antagonistic Behavior of Ligands

    Yoshimoto, Nobuko; Sakamaki, Yuta; Haeta, Minoru; Kato, Akira; Inaba, Yuka; Itoh, Toshimasa; Nakabayashi, Makoto; Ito, Nobutoshi; Yamamoto, Keiko

    Journal of Medicinal Chemistry (2012), 55 (9), 4373-4381CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    Previously, we reported that 22S-butyl-25,26,27-trinor-1α,24-dihydroxyvitamin D32 represents a new class of antagonist for the vitamin D receptor (VDR). The crystal structure of the ligand-binding domain (LBD) of VDR complexed with 2 showed the formation of a Bu pocket to accommodate the 22-Bu group and insufficient interactions between ligand 2 and the C-terminus of VDR. Here, we designed and synthesized new analogs 5a-c and evaluated their biol. activities to probe whether agonistic activity is recovered when the analog restores interactions with the C-terminus of VDR. Analogs 5a-c exhibited full agonistic activity in transactivation. Interestingly, 5c, which bears a 24-diethyl group, completely recovered agonistic activity, although 3c and 4c act as an antagonist and a weak agonist, resp. The crystal structures of VDR-LBD complexed with 3a, 4a, 5a, and 5c were solved, and the results confirmed that Bu pocket formation in VDR strongly affects the agonistic or antagonistic behaviors of ligands.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XlslGrtbg%253D&md5=777f75d0f91d274e3ec3fd39fd3272af

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    Yoshino, M. ; Eto, K. ; Takahashi, K. ; Ishihara, J. ; Hatakeyama, S. ; Ono, Y. ; Saito, H. ; Kubodera, N. Synthesis of 20-eldecalcitol [20-epi-1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3: 20-epi-ED-71]. Heterocycles 2010, 81 , 381– 394,  DOI: 10.3987/COM-09-11871

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    Synthetic studies on vitamin D analogs. 37. Synthesis of 20-epi-1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3: 20-epi-ed-71]

    Yoshino, Madoka; Eto, Kohei; Takahashi, Keisuke; Ishihara, Jun; Hatakeyama, Susumi; Ono, Yoshiyuki; Saito, Hitoshi; Kubodera, Noboru

    Heterocycles (2010), 81 (2), 381-394CODEN: HTCYAM; ISSN:0385-5414. (Japan Institute of Heterocyclic Chemistry)

    A convergent synthesis of the biol. interesting 20-epi-eldecalcitol (I) which possesses an inverted C-21 Me substituent at the 20-position of the side chain of 1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3 (eldecalcitol) was described.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsleisL8%253D&md5=02b9a8a8c99c74ff4240ea6fab2f58a3

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    Binderup, L. ; Latini, S. ; Binderup, E. ; Bretting, C. ; Calverley, M. ; Hansen, K. 20-epi-vitamin D3 analogues: a novel class of potent regulators of cell growth and immune responses. Biochem. Pharmacol. 1991, 42 , 1569– 1575,  DOI: 10.1016/0006-2952(91)90426-6

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    20-Epi-vitamin D3 analogs: a novel class of potent regulators of cell growth and immune responses

    Binderup, L.; Latini, S.; Binderup, E.; Bretting, C.; Calverley, M.; Hansen, K.

    Biochemical Pharmacology (1991), 42 (8), 1569-75CODEN: BCPCA6; ISSN:0006-2952.

    The 20-epi-vitamin D3 analogs are a novel class of vitamin D3 derivs., structurally related to 1α,25-dihydroxycholecalciferol (1α,25(OH)2D3). They are characterized by an altered stereochem. at carbon 20 in the side-chain. In vitro, these new analogs were found to be considerably more potent as regulators of growth and differentiation in the human histiocytic lymphoma cell line U 937 than 1α, 25(OH)2D3, despite a practically unchanged calcemic activity in vivo. The most potent analog, KH 1060, inhibited cell proliferation by 50% at 10-12 M (14,000 times more active than 1α,25(OH)2D3). At the same time, KH 1060 induced cell differentiation at concns. as low as 10-14M. In addn., the 20-epi-vitamin D3 analogs were found to be very potent inhibitors of T- lymphocyte proliferation induced by interleukin-1 or alloantigen. In this respect, they were several orders of magnitude more active than the potent immunosuppressive agent cyclosporin A (CyA). KH 1060, the most potent analog, inhibited interleukin-1-induced mouse thymocyte proliferation by 50% at 3 × 10-16 M and allogeneic stimulation of mouse spleen lymphocytes at 5 × 10-15 M. These effects were considered to be mediated by inhibition of interleukin-2 release from activated T-lymphocytes. The new analogs are of potential interest in the prevention of graft rejection and in the treatment of psoriasis, cancer and auto-immune disease.

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    Paaren, H. F. ; Schones, H. K. ; DeLuca, H. F. Synthesis of 1β-hydroxyvitamin D3 and 1β,25-dihydroxyvitamin D3 . J. Chem. Soc., Chem. Commun. 1977, 890– 892,  DOI: 10.1039/C39770000890

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    Synthesis of 1β-hydroxyvitamin D3 and 1β,25-dihydroxyvitamin D3

    Paaren, Herbert E.; Schones, Heinrich K.; DeLuca, Hector F.

    Journal of the Chemical Society, Chemical Communications (1977), (23), 890-2CODEN: JCCCAT; ISSN:0022-4936.

    MnO2 oxidn. of 1α-hydroxy- and 1α,25-dihydroxyvitamin D3 gave the oxoprevitamins I (R = H, OH, resp.) which on LiAlH4 redn. followed by treatment with EtOH at 80° gave 1β-hydroxy- (II; R = H) and 1β,25-dihydroxyvitamin D3 (II; R = OH), resp.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1cXksVeqtr8%253D&md5=5a23819a0a4f0fc3aa1ecabd2eb8b885

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    Napoli, J. L. ; Fivizzani, M. A. ; Schnoes, H. K. ; DeLuca, H. F. 1-Fluorovitamin D3, a vitamin D3 analogue more active on bone-calcium mobilization than on intestinal-calcium transport. Biochemistry 1979, 18 (9), 1641– 1646,  DOI: 10.1021/bi00576a001

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    1-Fluorovitamin D3, a vitamin D3 analog more active on bone-calcium mobilization than on intestinal-calcium transport

    Napoli, Joseph L.; Fivizzani, Mary A.; Schnoes, Heinrich K.; DeLuca, Hector F.

    Biochemistry (1979), 18 (9), 1641-6CODEN: BICHAW; ISSN:0006-2960.

    The chem. synthesis, spectral characterization, and biol. activity of 1-fluorovitamin D3 (I) [69879-46-5] are described. I was synthesized by direct fluorination of 1α-hydroxyvitamin D3 3β-acetate [69879-47-6], and characterized by UV, NMR, and mass spectroscopy. Similar responses of bone-Ca mobilization in vitamin D deficient rats were given by 200-300 ng of I and 25 ng of vitamin D3 [67-97-0]. Likewise, vitamin D3 and I provided the same degree of epiphyseal plate calcification in rachitic rats at daily doses of 20 and 270 ng, reesp. Thus, there appeared to be an approx. 10- to 15-fold difference in their ability to cause Ca and phosphate mobilization. However, about 1260 ng of I was necessary to produce the same degree of intestinal-Ca transport as 12.5 ng of vitamin D3, a difference of ∼ 100-fold. Therefore, relative to vitamin D3, I demonstrates at least partial selectivity for mediating Ca metab. in bone as opposed to mediating Ca metab. in intestine. I caused max. stimulation of bone-Ca mobilization and intestinal-Ca transport 24 h after a single, i.v. dose, like vitamin D3, but in contrast to 1α-hydroxyvitamin D3 which showed max. responses at about 12 h. Nephrectomized animals did not respond to I at doses higher than those which would cause significant responses in intact animals. Thus, I probably undergoes metab. in the kidney prior to manifesting physiol. activity.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1MXhvVSisLk%253D&md5=6c03923e6dcc24907e5f8ab3b285c1ad

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    Paaren, H. E. ; Fivizzani, M. A. ; Schnoes, H. K. ; De Luca, H. F. 1α,25-difluorovitamin D3: an inert vitamin D analog. Arch. Biochem. Biophys. 1981, 209 (2), 579– 583,  DOI: 10.1016/0003-9861(81)90315-5

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    1α,25-Difluorovitamin D3: an inert vitamin D analog

    Paaren, Herbert E.; Fivizzani, Mary A.; Schnoes, Heinrich K.; De Luca, Hector F.

    Archives of Biochemistry and Biophysics (1981), 209 (2), 579-83CODEN: ABBIA4; ISSN:0003-9861.

    1α,25-Difluorovitamin D3 (I) [78609-64-0] was synthesized by reacting 1α,25-dihydroxyvitamin D3 3-acetate [73809-41-3] with diethylaminosulfurtrifluoride [38078-09-0] followed by hydrolysis. Retention of configuration of the fluoro group in this reaction was demonstrated by phys. studies using 1α-fluoro and 1β-fluorovitamin D3 models. I had no vitamin D-like activity demonstrating the importance of 1α- and 25-hydroxylations of vitamin D for activity. However, I had no anti-25-hydroxylation activity and no antivitamin D activity. Since 25-fluorovitamin D3 has anti-25-hydroxylase activity, it appears the introduction of a fluoro group on the 1 position diminishes interaction of the vitamin D mol. with the 25-hydroxylase system.

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    Glebocka, A. ; Chiellini, G. A-ring analogs of 1,25-dihydroxyvitamin D3 . Arch. Biochem. Biophys. 2012, 523 (1), 48– 57,  DOI: 10.1016/j.abb.2011.11.010

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    A-ring analogs of 1,25-dihydroxyvitamin D3

    Glebocka, Agnieszka; Chiellini, Grazia

    Archives of Biochemistry and Biophysics (2012), 523 (1), 48-57CODEN: ABBIA4; ISSN:0003-9861. (Elsevier B.V.)

    A review. The growing interest in1α,25(OH)2D3, the hormonally active form of vitamin D3, has prompted numerous efforts to synthesize vitamin D analogs as potential therapeutic agents, and some of these are already on the market and in clin. development. Although most vitamin D prepns. developed thus far have focused on side-chain modifications, providing many useful analogs with high potency and selectivity, in recent years, modifications of the A-ring has attracted much attention because it can afford useful analogs exhibiting unique activity profiles as well. In this review we will focus on the current understanding of the relationship between selected modifications in the A-ring of the 1α,25(OH)2D3 mol., such as epimerization and/or substitution at C-1 and C-3, substitution at C-2, and removal of the 10,19-exocyclic methylene group, and their effect on biol. potency and selectivity. Finally, suggestions for the structure-based design of therapeutically valuable A-ring vitamin D analogs will conclude the review.

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    Ishida, H. ; Shimizu, M. ; Yamamoto, K. ; Iwasaki, Y. ; Yamada, S. ; Yamaguchi, K. Synthesis of 1-alkyl-1,25-dihydroxyvitamin D3 . J. Org. Chem. 1995, 60 , 1828– 1833,  DOI: 10.1021/jo00111a047

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    61

    Syntheses of 1-Alkyl-1,25-dihydroxyvitamin D3

    Ishida, Hiroki; Shimizu, Masato; Yamamoto, Keiko; Iwasaki, Yukiko; Yamada, Sachiko; Yamaguchi, Kentaro

    Journal of Organic Chemistry (1995), 60 (6), 1828-33CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)

    1-Alkylated analogs I [R = Me, Bu, R1 = OH; R = OH, R1 = Me, Bu] of 1α,25-(OH)2D3 were synthesized to investigate the effect of the alkyl group on the A-ring conformation and the biol. potency. The analogs were synthesized via two routes. In the first approach, alkylation of 4-phenyl-1,2,4-triazoline-3,5-dione adduct of 1-oxoprovitamin D was used as the key step to synthesize 1β-methyl-1α,25-(OH)2D3 (II) efficiently and stereoselectively. The photolysis of II, however, gave the desired previtamin D only as a minor product (<5%) and an unusual 1,10-bond cleavage product occurred in high yield (79%). As an alternative C(1)-epimeric pairs of 1-alkyl-1,25-(OH)2D3 were synthesized conveniently from 25-hydroxy-1-oxoprevitamin D3 by reaction with an alkyllithium followed by thermal isomerization. In the alkylation, the alkyllithium attacked the ketone preferentially from the side of the 3β-hydroxyl group to afford the 1β-alkyl-1α-hydroxy epimer in a 1.6-2.7 to 1 ratio over the 1α-alkyl-1β-hydroxy isomer. Introduction of a 1β-Me group to 1α,25-(OH)2D3, shifted the equil. between the two chair conformations of the A-ring preferentially to the side of the α-form (4:1) and reduced considerably the activity to bind to the receptor.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXktleks70%253D&md5=46bf0c5423adc9e1a7a111d9d3ef23b6

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    Sekimoto, H. ; Siu-Caldera, M. L. ; Weiskopf, A. ; Vouros, P. ; Muralidharan, K. R. ; Okamura, W. H. ; Uskokovic, M. R. ; Reddy, G. S. 1α,25-dihydroxy-3-epi-vitamin D3: in vivo metabolite of 1α,25-dihydroxyvitamin D3 in rats. FEBS Lett. 1999, 448 (2–3), 278– 282,  DOI: 10.1016/S0014-5793(99)00377-4

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    62

    1α,25-Dihydroxy-3-epi-vitamin D3: In vivo metabolite of 1α,25-dihydroxyvitamin D3 in rats

    Sekimoto, H.; Siu-Caldera, M.-L.; Weiskopf, A.; Vouros, P.; Muralidharan, K. R.; Okamura, W. H.; Uskokovic, M. R.; Reddy, G. S.

    FEBS Letters (1999), 448 (2,3), 278-282CODEN: FEBLAL; ISSN:0014-5793. (Elsevier Science B.V.)

    The authors recently identified 1α,25-dihydroxy-3-epi-vitamin D3 as a major in vitro metabolite of 1α,25-dihydroxyvitamin D3, produced in primary cultures of neonatal human keratinocytes. The authors now report the isolation of 1α,25-dihydroxy-3-epi-vitamin D3 from the serum of rats treated with pharmacol. doses of 1α,25-dihydroxyvitamin D3. 1,25-Dihydroxy-3-epi-vitamin D was identified through its co-migration with synthetic 1,25-dihydroxy-3-epi-vitamin D3 on both straight and reverse phase HPLC systems and by mass spectrometry. Along with 1α,25-dihydroxy-3-epi-vitamin D3, other previously known metabolites, namely, 1α,24(R),25-trihydroxyvitamin D3, 1α,25-dihydroxy-24-oxo-vitamin D3 and 1α,25-dihydroxyvitamin D3-26,23-lactone, were also identified. Thus, the authors' study for the first time provides direct evidence to indicate that 1α,25-dihydroxy-3-epi-vitamin D3 is an in vivo metabolite of 1α,25-dihydroxyvitamin D3 in rats.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXisV2ns7c%253D&md5=40b65b1fb41b45fe5ab77106a2653daa

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    Nakagawa, K. ; Kurobe, M. ; Ozono, K. ; Konno, K. ; Fujishima, T. ; Takayama, H. ; Okano, T. Novel ring A stereoisomers of 2-methyl-1α,25-dihydroxyvitamin D3 and 2-methyl-20-epi-1α,25-dihydroxyvitamin D3: transactivation of target genes and modulation of differentiation in human promyelocytic leukemia (HL-60) cells. Biochem. Pharmacol. 2000, 59 (6), 691– 702,  DOI: 10.1016/S0006-2952(99)00357-3

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    Novel ring A stereoisomers of 2-Methyl-1α,25-dihydroxyvitamin D3 and 2-Methyl-20-epi-1α,25-dihydroxyvitamin D3: transactivation of target genes and modulation of differentiation in human promyelocytic leukemia (HL-60) cells

    Nakagawa, K.; Kurobe, M.; Ozono, K.; Konno, K.; Fujishima, T.; Takayama, H.; Okano, T.

    Biochemical Pharmacology (2000), 59 (6), 691-702CODEN: BCPCA6; ISSN:0006-2952. (Elsevier Science Inc.)

    The authors evaluated the biol. activity of two sets of ring A stereoisomers of 2-methyl-1α,25-dihydroxyvitamin D3 (2-methyl-1α,25(OH)2D3) and 2-methyl-20-epi-1α,25-dihydroxyvitamin D3 (2-methyl-20-epi-1α,25(OH)2D3) in terms of the following: transactivation of a rat 25-hydroxyvitamin D3-24-hydroxylase gene promoter including two vitamin D response elements (VDREs) and a human osteocalcin gene promoter including a VDRE in transfected human osteosarcoma (MG-63) cells; a vitamin D receptor (VDR)-mediated response using a VDR-GAL4 one-hybrid luciferase reporter system and a retinoid X receptor α (RXRα)-mediated response using an expressed VDR/RXRα-GAL4 modified two-hybrid luciferase reporter system in transfected human epithelioid carcinoma, cervix (HeLa) cells; and modulation of cell surface CD11b antigen expression in human leukemia (HL-60) cells. All the diastereomers of both analogs exhibited unique biol. activity profiles depending upon the configurations of the C-1 and C-3 hydroxyl groups, the C-2 Me group in ring A, and the C-20 Me group in the side chain. Of the eight possible diastereomers of the 2-Me analogs, 2α-methyl-1α,25(OH)2D3 was the most potent and exhibited comparable or even greater biol. potency than 1α,25(OH)2D3. Of the eight possible diastereomers of the 2-methyl-20-epi analogs, 2α-methyl-20-epi-1α,25(OH)2D3 was the most potent and exhibited 100- to 200-fold higher transcriptional potencies than 1α,25(OH)2D3 and exceptionally high cell regulatory activities. 2β-Methyl-20-epi-1α,25(OH)2D3 was nearly as potent as its 2-epimer, 2α-methyl-20-epi-1α,25(OH)2D3, whereas its 20-epimer, 2β-methyl-1α,25(OH)2D3, was almost completely biol. inactive. In these respects, it can be postulated that the double modification of 2-Me substitution and 20-epimerization to 1α,25(OH)2D3 induces remarkable changes in a VDR/RXRα/VDRE-mediated signaling response and greatly enhances biol. activity. The other striking finding was that 2β-methyl-20-epi-3-epi-1β,25(OH)2D3 is transcriptionally more active than 1α,25(OH)2D3 despite lacking the 1α-hydroxyl group, which was believed to be essential for expressing VDR-mediated gene transcription. Since the C-20 natural counterpart, 2β-methyl-3-epi-1β,25(OH)2D3, was almost completely biol. inactive, 20-epimerization is probably responsible for activation of gene expression. Although earlier extensive structure-activity studies of vitamin D analogs showed stereochem. at the C-1, C-3, and C-20 of 1α,25(OH)2D3 to be the key structural motif for vitamin D action, the authors' results clearly demonstrated that stereochem. at the C-2 is also an important structural motif for vitamin D action and imply that 2-Me substitution possibly induces conformational changes in ring A depending upon the combinations of configurations of the C-1 and C-3 hydroxyl groups with C-20 stereochem. Consequently, several of these analogs exhibit exceptionally high or unexpected biol. activities at the mol. and cellular levels. These results suggest that 2-Me substitution together with alterations of stereochem. in both ring A and the side chain of 1α,25(OH)2D3 will provide useful analogs for structure-activity studies and development of therapeutic agents with unique biol. activity profiles.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXhtFalt70%253D&md5=32cdc6c04fce094e56a0b8215653bace

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    Suhara, Y. ; Nihei, K. I. ; Tanigawa, H. ; Fujishima, T. ; Konno, K. ; Nakagawa, K. ; Okano, T. ; Takayama, H. Syntheses and biological evaluation of novel 2α-substituted 1α,25-dihydroxyvitamin D3 analogues. Bioorg. Med. Chem. Lett. 2000, 10 (10), 1129– 1132,  DOI: 10.1016/S0960-894X(00)00189-X

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    64

    Syntheses and biological evaluation of novel 2α-substituted 1α,25-dihydroxyvitamin D3 analogues

    Suhara, Yoshitomo; Nihei, Ken-Ichi; Tanigawa, Hirokazu; Fujishima, Toshie; Konno, Katsuhiro; Nakagawa, Kimie; Okano, Toshio; Takayama, Hiroaki

    Bioorganic & Medicinal Chemistry Letters (2000), 10 (10), 1129-1132CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)

    Novel 2α-substituted 1α,25-dihydroxyvitamin D3 analogs were efficiently synthesized and their biol. activities were evaluated. 2α-Methyl-1α,25-dihydroxyvitamin D3, whose unique biol. activities were previously reported, was modified to 2α-alkyl (Et and propyl) and 2α-hydroxyalkyl (hydroxymethyl, hydroxyethyl, and hydroxypropyl) analogs by elongation of the alkyl chain and/or introduction of a terminal hydroxyl group. 2α-(3-Hydroxypropyl)-1α,25-dihydroxyvitamin D3 exhibited an exceptionally potent calcium-regulating effect and a unique activity profile.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXjsl2lur0%253D&md5=d35266d128601a0c218004c3b2d22ed0

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    Perlman, K. L. ; Swenson, R. E. ; Paaren, H. E. ; Schnoes, H. K. ; DeLuca, H. F. Novel synthesis of 19-nor-vitamin D compounds. Tetrahedron Lett. 1991, 32 , 7663– 7666,  DOI: 10.1016/0040-4039(91)80559-O

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    Novel synthesis of 19-nor-vitamin D compounds

    Perlman, Kato L.; Swenson, Rolf E.; Paaren, Herbert E.; Schnoes, Heinrich K.; DeLuca, Hector F.

    Tetrahedron Letters (1991), 32 (52), 7663-6CODEN: TELEAY; ISSN:0040-4039.

    1α,25-Dihydroxy-19-norvitamin D3 (I) was prepd. efficiently in a convergent synthesis starting with (-)-quinic acid (II). The key step involved a Horner-Wittig condensation of ketone III with the phosphine oxide IV derived from II.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38Xht12gtbw%253D&md5=ffc0d134196438f35d4970e1651e08b5

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    Bouillon, R. ; Sarandeses, L. A. ; Allewaert, K. ; Zhao, J. ; Mascarenas, J. L. ; Mouriño, A. ; Vrielynck, S. ; de Clercq, P. ; Vandewalle, M. Biologic activity of dihydroxylated 19-nor-(pre)vitamin D3 . J. Bone Miner. Res. 1993, 8 (8), 1009– 1015,  DOI: 10.1002/jbmr.5650080815

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    Biologic activity of dihydroxylated 19-nor-(pre)vitamin D3

    Bouillon, Roger; Sarandeses, Luis A.; Allewaert, Katrien; Zhao, Jie; Mascarenas, J. Luis; Mourino, Antonio; Vrielynck, Sara; De Clercq, Pierre; Vandewalle, Maurits

    Journal of Bone and Mineral Research (1993), 8 (8), 1009-15CODEN: JBMREJ; ISSN:0884-0431.

    Vitamin D3 and its hydroxylated metabolites are normally in thermal equil. with their previtamin D isomers. To evaluate the biol. activity of 1α,25-dihydroxyprevitamin D3 (I), 19-nor analogs of I were synthesized because the absence of a C19 methylene group prevents the isomerization of these analogs. The affinity of 1α,25-(OH)2D3-19-nor-D3 (II) for the intestinal vitamin D receptor and plasma vitamin D-binding protein (DBP) was mildly decreased [30 and 20% of the affinity of 1α,25-dihydroxyvitamin D3 (III), resp.], but the affinity of 1α,25-(OH)2-19-nor-previtamin D3 (IV) was only 1 and 6% of that of III for the receptor and DBP, resp. The in vitro effects on human promyeloid leukemia (HL-60 cell) differentiation and osteocalcin secretion by human osteosarcoma (MG-63) cells by II were nearly identical to those of III, whereas IV showed poor activity (2%). The in vivo calcemic effects of both analogs, studied in vitamin D-deficient chicks treated for 10 consecutive days with the analogs, showed no activity of IV and reduced calcemic effects (≤10%) of II. Evidently, the previtamin D form of III loses most of its biol. activity in vitro and in vivo.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXjtFKjsLw%253D&md5=98cfa0d459d57c1bb3c34a5daf0adbef

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    Sicinski, R. R. ; Perlman, K. L. ; DeLuca, H. F. Synthesis and biological activity of 2-hydroxy and 2-alkoxy analogs of 1α,25-dihydroxy-19-norvitamin D3 . J. Med. Chem. 1994, 37 (22), 3730– 3738,  DOI: 10.1021/jm00048a009

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    67

    Synthesis and Biological Activity of 2-Hydroxy and 2-Alkoxy Analogs of 1α,25-Dihydroxy-19-norvitamin D3

    Sicinski, Rafal R.; Perlman, Kato L.; DeLuca, Hector F.

    Journal of Medicinal Chemistry (1994), 37 (22), 3730-8CODEN: JMCMAR; ISSN:0022-2623.

    1α,2α,25-Trihydroxy-19-norvitamin D3 I (X = OH, Y = H), 1α,2β,25-trihydroxy-19-norvitamin D3 I (X = H, Y = OH), and their alkoxy analogs were efficiently prepd. in a convergent synthesis, starting with (-)-quinic acid and a Windaus-Grundmann type ketone. Configurations of the A-ring fragment substituents were detd. by 1H,1H COSY 2D spectra and 1H NOE difference spectroscopy. The new analogs exhibited selective activity in stimulating intestinal calcium transport while having little or no activity in mobilizing bone calcium. They also showed HL-60-differentiating activity equal to or 10 times lower than that of 1α,25-dihydroxyvitamin D3.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXhtVeqt7s%253D&md5=6ab50bce0b733215baeea32f684a257c

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    Yamamoto, H. ; Shevde, N. K. ; Warrier, A. ; Plum, L. A. ; DeLuca, H. F. ; Pike, J. W. 2-Methylene-19-nor-(20S)-1,25-dihydroxyvitamin D3 potently stimulates gene-specific DNA binding of the vitamin D receptor in osteoblasts. J. Biol. Chem. 2003, 278 (34), 31756– 31765,  DOI: 10.1074/jbc.M304737200

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    2-Methylene-19-nor-(20S)-1,25-dihydroxyvitamin D3 potently stimulates gene-specific DNA binding of vitamin D receptor in osteoblasts

    Yamamoto, Hironori; Shevde, Nirupama K.; Warrier, Anjali; Plum, Lori A.; DeLuca, Hector F.; Pike, J. Wesley

    Journal of Biological Chemistry (2003), 278 (34), 31756-31765CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)

    2-Methylene-19-nor-(20S)-1,25-dihydroxyvitamin D3 (2MD) is a highly potent analog of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) whose actions are mediated through the vitamin D receptor (VDR). The authors have replicated this increased potency of 2MD in vitro using osteoblastic cells and explored its underlying mol. mechanism. 2MD stimulates the expression of several vitamin D-sensitive genes including 25-hydroxyvitamin D3-24 hydroxylase (Cyp24), osteopontin and receptor activator of NFκB ligand and suppresses osteoprotegerin at concns. two logs lower than that for 1,25(OH)2D3. 2MD is also more potent in stimulating transfected chimeric reporter genes under either Cyp24 or the osteocalcin promoter control. Enhanced potency is retained regardless of medium serum content. Interestingly, the uptake of both 1,25(OH)2D3 and 2MD into cells is similar, as is their rapid assocn. with the VDR. This indicates that comparable levels of occupied VDR do not elicit equiv. levels of transactivation. Using chromatin immunopptn. (ChIP), however, the authors obsd. a strong correlation between DNA-bound receptor and the level of induced transcription suggesting a 2MD-induced increase in affinity of the VDR for DNA. Addnl. studies using a mammalian two-hybrid system and ChIP indicate that 2MD is also more potent in promoting interaction with RXR and the coactivators SRC-1 and DRIP205. Finally, protease digestion studies revealed a unique VDR conformation in the presence of 2MD. These studies suggest that the mol. mechanism of 2MD potency is due to its ability to promote enhanced levels of specific DNA binding by the VDR and could suggest possible explanations for the tissue- and gene-selective actions of 2MD.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXmsVOntLc%253D&md5=65894077d5237a8544230c3066f7eb07

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    Williams, S. ; Bledsoe, R. K. ; Collins, J. L. ; Boggs, S. ; Lambert, M. H. ; Miller, A. B. ; Moore, J. ; McKee, D. D. ; Moore, L. ; Nichols, J. ; Parks, D. ; Watson, M. ; Wisely, B. ; Willson, T. M. X-ray crystal structure of the liver X receptor beta ligand binding domain: regulation by a histidine-tryptophan switch. J. Biol. Chem. 2003, 278 (29), 27138– 27143,  DOI: 10.1074/jbc.M302260200

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    X-ray Crystal Structure of the Liver X Receptor β Ligand Binding Domain: Regulation by a Histidine-Tryptophan Switch

    Williams, Shawn; Bledsoe, Randy K.; Collins, Jon L.; Boggs, Sharon; Lambert, Millard H.; Miller, Ann B.; Moore, John; McKee, David D.; Moore, Linda; Nichols, Jason; Parks, Derek; Watson, Mike; Wisely, Bruce; Willson, Timothy M.

    Journal of Biological Chemistry (2003), 278 (29), 27138-27143CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)

    The x-ray crystal structures of the human liver X receptor β ligand binding domain complexed to sterol and nonsterol agonists revealed a perpendicular histidine-tryptophan switch that holds the receptor in its active conformation. Hydrogen bonding interactions with the ligand act to position the His-435 imidazole ring against the Trp-457 indole ring, allowing an electrostatic interaction that holds the AF2 helix in the active position. The neutral oxysterol 24(S),25-epoxycholesterol accepts a hydrogen bond from His-435 that positions the imidazole ring of the histidine above the pyrrole ring of the tryptophan. In contrast, the acidic T0901317 hydroxyl group makes a shorter hydrogen bond with His-435 that pulls the imidazole over the electron-rich benzene ring of the tryptophan, possibly strengthening the electrostatic interaction. Point mutagenesis of Trp-457 supports the observation that the ligand-histidine-tryptophan coupling is different between the two ligands. The lipophilic liver X receptor ligand-binding pocket is larger than the corresponding steroid hormone receptors, which allows T0901317 to adopt two distinct conformations. These results provide a mol. basis for liver X receptor activation by a wide range of endogenous neutral and acidic ligands.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXltlKqu74%253D&md5=e13e5b372563ed6854eb03973bcbe391

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    Tsugawa, N. ; Nakagawa, K. ; Kurobe, M. ; Ono, Y. ; Kubodera, N. ; Ozono, K. ; Okano, T. In vitro biological activities of a series of 2 beta-substituted analogues of 1α,25-dihydroxyvitamin D3 . Biol. Pharm. Bull. 2000, 23 (1), 66– 71,  DOI: 10.1248/bpb.23.66

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    In vitro biological activities of a series of 2β-substituted analogs of 1α,25-dihydroxyvitamin D3

    Tsugawa, Naoko; Nakagawa, Kimie; Kurobe, Mayuko; Ono, Yoshiyuki; Kubodera, Noboru; Ozono, Keiichi; Okano, Toshio

    Biological & Pharmaceutical Bulletin (2000), 23 (1), 66-71CODEN: BPBLEO; ISSN:0918-6158. (Pharmaceutical Society of Japan)

    Biol. activities of a series of 2β-substituted analogs of 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] were evaluated in vitro in terms of their binding affinity with regard to calf thymus cytosolic vitamin D receptor (VDR) and rat plasma vitamin D-binding protein (DBP). Addnl., reporter gene luciferase activities using either a rat 25-hydroxyvitamin D3-24-hydroxylase gene promoter, including two vitamin D-responsive elements (VDREs), in transfected rat osteoblast-like ROS17/2.8 cells, or a human VDR-GAL4 modified two-hybrid system in transfected human epitheloid carcinoma, cervix HeLa cells were examd. Binding affinity for VDR, transactivation potency on the target gene and VDR-mediated gene regulation of the hydroxyalkyl and hydroxyalkoxy 2β-substituted analogs were almost comparable to those of 1α,25(OH)2D3, while the alkyl and alkenyl analogs were much less active than 1α,25(OH)2D3. This study investigated the biol. evaluation of a series of 2β-substituted analogs at the mol. level, with regard to the structural differences of alkyl, alkenyl, hydroxyalkyl, hydroxyalkoxy, alkoxy, hydroxy and chloro substituents at the 2β-position of 1α,25(OH)2D3.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXmvFWqsw%253D%253D&md5=771a430909d389c9ceaa1520e12a722e

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    Shimizu, M. ; Miyamoto, Y. ; Kobayashi, E. ; Shimazaki, M. ; Yamamoto, K. ; Reischl, W. ; Yamada, S. Synthesis and biological activities of new 1α,25-dihydroxy-19norvitamin D3 analogs with modifications in both A-ring and the side chain. Bioorg. Med. Chem. 2006, 14 , 4277– 4294,  DOI: 10.1016/j.bmc.2006.01.061

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    Synthesis and biological activities of new 1α,25-dihydroxy-19-norvitamin D3 analogs with modifications in both the A-ring and the side chain

    Shimizu, Masato; Miyamoto, Yukiko; Kobayashi, Emi; Shimazaki, Mika; Yamamoto, Keiko; Reischl, Wolfgang; Yamada, Sachiko

    Bioorganic & Medicinal Chemistry (2006), 14 (12), 4277-4294CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)

    In a series of studies on structure-activity relationships of 2-substituted 19-norvitamin D analogs, we found that 1α,25-dihydroxy-19-norvitamin D3 analogs with 2β-hydroxyethoxy or 2E-hydroxyethylidene moieties show strong binding affinity for the vitamin D receptor (VDR) as well as marked transcriptional activity. To further examine the effects of side chain structure on the activity of 2-substituted 19-norvitamin D analogs, we have synthesized new 19-norvitamin D3 analogs with modifications in both the A-ring at the C(2) position and the side chain. The side chains of these analogs contained a double bond between C(22) and C(23) or an oxygen atom at C(22). The biol. activity of the analogs was evaluated in vitro. All the side chain-modified analogs were less active than 1α,25-dihydroxyvitamin D3 and the parent compds. I [X2 = CHCH2OH-(E), -(Z), R21 = β-H, R22 = (CH2)3CMe2OH] and II [R2 = α-, β-H, R21 = β-H, R22 = (CH2)3CMe2OH] possessing a natural 20R-configuration in binding to the VDR, but, except for the (20R)-22-oxa analogs I [X2 = CHCH2OH-(E), -(Z), R21 = α-H, R22 = O(CH2)2CMe2OH] and II [R2 = α-, β-H, R21 = α-H, R22 = O(CH2)2CMe2OH], were significantly more potent in transcriptional activity. Of the side-chain-modified analogs the 2β-hydroxyethoxy- and 2E-hydroxyethylidene-22,24-diene-24a,26a,27a-trihomo analogs showed markedly higher transcriptional activity (25- and 17.5-fold, resp.) compared with 1α,25-dihydroxyvitamin D3. Elongation of the side chain at the C-24, C-26, and C-27 positions and introduction of a 22,24-diene moiety strongly increased transcriptional activity, as seen in the 20-epi analogs I [X2 = CHCH2OH-(E), -(Z), R21 = α-H, R22 = (CH2)3CMe2OH] and II [R2 = α-, β-H, R21 = α-H, R22 = (CH2)3CMe2OH].

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    Posner, G. H. ; Lee, J. K. ; Wang, Q. ; Peleg, S. ; Burke, M. ; Brem, H. ; Dolan, P. ; Kensler, T. W. Noncalcemic, antiproliferative, transcriptionally active, 24-fluorinated hybrid analogues of the hormone 1α,25-dihydroxyvitamin D3: synthesis and preliminary biological evaluation. J. Med. Chem. 1998, 41 , 3008– 3014,  DOI: 10.1021/jm980031t

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    Noncalcemic, Antiproliferative, Transcriptionally Active, 24-Fluorinated Hybrid Analogs of the Hormone 1α,25-Dihydroxyvitamin D3. Synthesis and Preliminary Biological Evaluation

    Posner, Gary H.; Lee, Jae Kyoo; Wang, Qiang; Peleg, Sara; Burke, Martin; Brem, Henry; Dolan, Patrick; Kensler, Thomas W.

    Journal of Medicinal Chemistry (1998), 41 (16), 3008-3014CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    Four new hybrid analogs of 1α,25-dihydroxyvitamin D3 have been synthesized in a convergent manner by joining A-ring and C,D-ring fragments. Each hybrid analog, having a noncalcemic 1-hydroxymethyl group and a potentiating 16-ene 24,24-difluorinated C,D-ring side chain, was designed to be lipophilic and inert toward 24-hydroxylase enzyme catabolism. Each hybrid analog with 1β,3α-substituent stereochem. showed a pharmacol. desirable combination of in vitro high antiproliferative activity in two different cell lines and high transcriptional activity with also low calcemic activity in vivo.

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    Peleg, S. ; Ismail, A. ; Uskokovic, M. R. ; Avnur, Z. Evidence for tissue- and cell-type selective activation of the vitamin D receptor by Ro-26-9228, a noncalcemic analog of vitamin D3 . J. Cell. Biochem. 2003, 88 (2), 267– 273,  DOI: 10.1002/jcb.10344

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    73

    Evidence for tissue- and cell-type selective activation of the vitamin D receptor by Ro-26-9228, a noncalcemic analog of vitamin D3

    Peleg, Sara; Ismail, Ayesha; Uskokovic, Milan R.; Avnur, Zafrira

    Journal of Cellular Biochemistry (2003), 88 (2), 267-273CODEN: JCEBD5; ISSN:0730-2312. (Wiley-Liss, Inc.)

    The authors' recent studies have shown that the vitamin D analog Ro-26-9228 restores bone mineral d. without inducing hypercalcemia in osteopenic rats. The authors' ex vivo expts. demonstrated that the analog upregulated gene expression in trabecular bone but not in the duodenum of female rats. The authors examd. the mechanism for the tissue selectivity of Ro-26-9228 in Caco-2, a human cell line of intestinal origin, and hFOB, and a human fetal osteoblast cell line. The authors found that the abilities of Ro-26-9228 and the natural hormone, 1,25-dihydroxyvitamin D3 (1,25D3) to induce VDRE-reporter gene expression in transiently transfected human osteoblasts are similar. In contrast, in Caco-2 cells, Ro-26-9228 induces 40-fold less reporter gene expression than 1,25D3 does. The authors also examd. the abilities of the vitamin D receptor (VDR)-ligand complexes from these two cell lines to interact with partners of transcription (glucocorticoid receptor-interacting protein, VDR-interacting protein, and retinoid X receptor), in pull-down assays. These assays revealed that 1,25D3 induces similar levels of interaction of these co-factors with VDR from both osteoblasts and intestinal cells. In contrast, Ro-26-9228 induces significant interaction of VDR from osteoblast cells with these co-factors, but less of VDR from Caco-2 cells. These results suggest that the cellular environment of intestinal cells, unlike that of osteoblasts, represses the ability of VDR-Ro-26-9228 complexes to interact with transcription partners.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXntlylug%253D%253D&md5=3248595f2a02733c330d02bb45a57e6f

  74. 74

    Flores, A. ; Sicinski, R. R. ; Grzywacz, P. ; Thoden, J. B. ; Plum, L. A. ; Clagett-Dame, M. ; DeLuca, H. F. A 20S combined with a 22R configuration markedly increases both in vivo and in vitro biological activity of 1α,25-dihydroxy-22-methyl-2-methylene-19-norvitamin D3 . J. Med. Chem. 2012, 55 (9), 4352– 4366,  DOI: 10.1021/jm300187x

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    74

    A 20S Combined with a 22R Configuration Markedly Increases both in Vivo and in Vitro Biological Activity of 1α,25-Dihydroxy-22-methyl-2-methylene-19-norvitamin D3

    Flores, Agnieszka; Sicinski, Rafal R.; Grzywacz, Pawel; Thoden, James B.; Plum, Lori A.; Clagett-Dame, Margaret; DeLuca, Hector F.

    Journal of Medicinal Chemistry (2012), 55 (9), 4352-4366CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    Six new analogs of 1α,25-dihydroxy-19-norvitamin D3 were prepd. by a convergent synthesis applying the Wittig-Horner reaction as a key step. The influence of Me groups at C-22 on their biol. activity was examd. It was established that both in vitro and in vivo activity is strongly dependent on the configuration of the stereogenic centers at C-20 and C-22. Introduction of the second Me group at C-22 (I and II) generates the compds. that are slightly more potent than 1α,25-(OH)2D3 in the in vitro tests but much less potent in vivo. The greatest in vitro and in vivo biol. activity was achieved when the C-20 is in the S configuration and the C-22 is in the R configuration. The building blocks for the synthesis, the resp. (20R,22R)-, (20R,22S)-, (20S,22R)-, and (20S,22S)-diols, were obtained by fractional crystn. of mixts. of the corresponding diastereomers. Structures and abs. configurations of four intermediate diols as well as analogs three products were confirmed by the X-ray crystallog.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xltl2ht74%253D&md5=9ed6316695d2c86a9b9e43736513d36a

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    Sibilska, I. K. ; Szybinski, M. ; Sicinski, R. R. ; Plum, L. A. ; DeLuca, H. F. Synthesis and biological activity of 2-methylene analogues of calcitriol and related compounds. J. Med. Chem. 2015, 58 (24), 9653– 9662,  DOI: 10.1021/acs.jmedchem.5b01295

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    75

    Synthesis and Biological Activity of 2-Methylene Analogues of Calcitriol and Related Compounds

    Sibilska, Izabela K.; Szybinski, Marcin; Sicinski, Rafal R.; Plum, Lori A.; DeLuca, Hector F.

    Journal of Medicinal Chemistry (2015), 58 (24), 9653-9662CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    In an attempt to prep. vitamin D analogs that are superagonists, (20R)- and (20S)-isomers of 1α-hydroxy-2-methylenevitamin D3 and 1α,25-dihydroxy-2-methylenevitamin D3 have been synthesized. To prep. the desired A-ring dienyne fragment, two different approaches were used, both starting from the (-)-quinic acid. The obtained deriv. was subsequently coupled with the C,D-ring enol triflates derived from the corresponding Grundmann ketones, using the Sonogashira reaction. Moreover, (20R)- and (20S)-1α,25-dihydroxy-2-methylenevitamin D3 compds. with an (5E)-configuration were prepd. by iodine catalyzed isomerization. All four 2-methylene analogs of the native hormone were characterized by high in vitro activity. As expected, the 25-desoxy analogs were much less potent. Among the synthesized compds., two of them, 1α,25-dihydroxy-2-methylenevitamin D3 and its C-20 epimer, were found to be almost as active as 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3 (2MD) on bone but more active in intestine.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVKmsrjM&md5=218783eea598e5aeb5385ff2b5bfc75b

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    Sawada, D. ; Tsukuda, Y. ; Saito, H. ; Kakuda, S. ; Takimoto-Kamimura, M. ; Ochiai, E. ; Takenouchi, K. ; Kittaka, A. Development of 14-epi-19-nortachysterol and its unprecedented binding configuration for the human vitamin D receptor. J. Am. Chem. Soc. 2011, 133 , 7215– 7221,  DOI: 10.1021/ja201481j

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    76

    Development of 14-epi-19-Nortachysterol and Its Unprecedented Binding Configuration for the Human Vitamin D Receptor

    Sawada, Daisuke; Tsukuda, Yuya; Saito, Hiroshi; Kakuda, Shinji; Takimoto-Kamimura, Midori; Ochiai, Eiji; Takenouchi, Kazuya; Kittaka, Atsushi

    Journal of the American Chemical Society (2011), 133 (18), 7215-7221CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

    In the study of the synthesis of 14-epi-19-norprevitamin D3, e.g., I, we found 14-epi-19-nortachysterol derivs., e.g., II, through C6,7-cis/trans isomerization. We also succeeded in their chem. synthesis and revealed their marked stability and potent VDR binding affinity. To the best of our knowledge, this is the first isolation of stable tachysterol analogs. Surprisingly, 14-epi-19-nortachysterol derivs. exhibited an unprecedented binding configurations for the ligand binding pocket in hVDR, C5,6-s-trans and C7,8-s-trans triene configurations, which were opposite the natural C7,8-ene-configuration of 1α,25(OH)2D3.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXkvVCltLg%253D&md5=4e3ee0540865e6d9a9bfe0c4881ef622

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    Laverny, G. ; Penna, G. ; Uskokovic, M. ; Marczak, S. ; Maehr, H. ; Jankowski, P. ; Ceailles, C. ; Vouros, P. ; Smith, B. ; Robinson, M. ; Reddy, G. S. ; Adorini, L. Synthesis and anti-inflammatory properties of 1α,25-dihydroxy-16-ene-20-cyclopropyl-24-oxo-vitamin D3, a hypocalcemic, stable metabolite of 1α,25-dihydroxy-16-ene-20-cyclopropyl-vitamin D3 . J. Med. Chem. 2009, 52 (8), 2204– 2213,  DOI: 10.1021/jm801365a

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    Synthesis and Anti-inflammatory Properties of 1α,25-Dihydroxy-16-ene-20-cyclopropyl-24-oxo-vitamin D3, a Hypocalcemic, Stable Metabolite of 1α,25-Dihydroxy-16-ene-20-cyclopropyl-vitamin D3

    Laverny, Gilles; Penna, Giuseppe; Uskokovic, Milan; Marczak, Stanislaw; Maehr, Hubert; Jankowski, Pawel; Ceailles, Caroline; Vouros, Paul; Smith, Brenden; Robinson, Matthew; Reddy, G. Satyanarayana; Adorini, Luciano

    Journal of Medicinal Chemistry (2009), 52 (8), 2204-2213CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    1α,25(OH)2-16-ene-20-cyclopropyl-vitamin D3 (I) is several fold more potent than the natural hormone 1α,25-dihydroxyvitamin D3 as an anti-inflammatory agent. Here, we have further analyzed the anti-inflammatory properties of I, confirming it as the most potent analog tested within this family. We then detd. the structures of all the natural metabolites of I, including the 24-oxo metabolite II, and carried out its synthesis. A comparison of I with II showed a similar induction of the primary VDR target genes CYP24A1 and CAMP and comparable anti-inflammatory properties as revealed by a similar inhibition of TNF-α, IL-12/23p40, IL-6, and IFN-γ prodn. Interestingly, II displays a 3-fold lower calcemic activity in vivo compared to I. Collectively, these findings indicate that the strong potency of I can be explained by the accumulation of its stable 24-oxo metabolite, which shows immunoregulatory and anti-inflammatory properties superimposable to those exerted by I itself.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjsFKksbY%253D&md5=14a52682534a35613971472350082480

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    Fujii, S. ; Masuno, H. ; Taoda, Y. ; Kano, A. ; Wongmayura, A. ; Nakabayashi, M. ; Ito, N. ; Shimizu, M. ; Kawachi, E. ; Hirano, T. ; Endo, Y. ; Tanatani, A. ; Kagechika, H. Boron cluster-based development of potent nonsecosteroidal vitamin D receptor ligands: direct observation of hydrophobic interaction between protein surface and carborane. J. Am. Chem. Soc. 2011, 133 (51), 20933– 20941,  DOI: 10.1021/ja208797n

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    78

    Boron cluster-based development of potent nonsecosteroidal vitamin D receptor ligands: direct observation of hydrophobic interaction between protein surface and carborane

    Fujii, Shinya; Masuno, Hiroyuki; Taoda, Yoshiyuki; Kano, Atsushi; Wongmayura, Angsuma; Nakabayashi, Makoto; Ito, Nobutoshi; Shimizu, Masato; Kawachi, Emiko; Hirano, Tomoya; Endo, Yasuyuki; Tanatani, Aya; Kagechika, Hiroyuki

    Journal of the American Chemical Society (2011), 133 (51), 20933-20941CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

    The design and synthesis of a novel vitamin D receptor (VDR) agonist is described, whose hydrophobic core structure is p-carborane (H2Q, 1,12-C2B10H12), featuring an icosahedral carbon-contg. boron cluster having remarkable thermal and chem. stability and a characteristically hydrophobic B-H surface. This carborane-based VDR ligands HOCH2(CH2)nCHOHCH2OCH2(CH2)m-1,12-C2B10H10(CH2)4CEt2OH (m, n = 0, 1) exhibited moderate vitamin D activity, comparable to that of the natural hormone, despite its simple and flexible structure. X-ray structure anal. provided direct evidence that the carborane cage binds to the hydrophobic surface of the ligand-binding pocket of the receptor, promoting transition to the active conformation. These results indicate that the spherical B-H surface of carborane can function efficiently as a hydrophobic anchor in binding to the receptor surface, thereby allowing induced fitting of the three essential hydroxyl groups on the alkyl chains to the appropriate positions for interaction with the VDR binding site, despite the entropic disadvantage of the flexible structure. We suggest that carborane structure is a promising option in the design of novel drug candidates.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVarsr3O&md5=46466dbcc4c9152f91b6a59d1b1e143d

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    Boehm, M. F. ; Fitzgerald, P. ; Zou, A. ; Elgort, M. G. ; Bischoff, E. D. ; Mere, L. ; Mais, D. E. ; Bissonnette, R. P. ; Heyman, R. A. ; Nadzan, A. M. ; Reichman, M. ; Allegretto, E. A. Novel nonsecosteroidal vitamin D mimics exert VDR-modulating activities with less calcium mobilization than 1,25-dihydroxyvitamin D3 . Chem. Biol. 1999, 6 (5), 265– 275,  DOI: 10.1016/S1074-5521(99)80072-6

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    Novel nonsecosteroidal vitamin D mimics exert VDR-modulating activities with less calcium mobilization than 1,25-dihydroxyvitamin D3

    Boehm, Marcus F.; Fitzgerald, Patrick; Zou, Aihua; Elgort, Marc G.; Bischoff, Eric D.; Mere, Lora; Mais, Dale E.; Bissonnette, Reid P.; Heyman, Richard A.; Nadzan, Alex M.; Reichman, Melvin; Allegretto, Elizabeth A.

    Chemistry & Biology (1999), 6 (5), 265-275CODEN: CBOLE2; ISSN:1074-5521. (Current Biology Publications)

    The secosteroid 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) acts through the vitamin D receptor (VDR) to elicit many activities that make it a promising drug candidate for the treatment of a no. of diseases, including cancer and psoriasis. Clin. use of 1,25(OH)2D3 has been limited by hypercalcemia elicited by pharmacol. EDs. It was hypothesized that structurally distinct, nonsecosteroidal mimics of 1,25(OH)2D3 might have different activity profiles from vitamin D analogs, and set out to discover such compds. by screening small-mol. libraries. A bis-Ph deriv. was found to activate VDR in a transactivation screening assay. Addnl. related compds. were synthesized that mimicked various activities of 1,25(OH)2D3, including growth inhibition of cancer cells and keratinocytes, as well as induction of leukemic cell differentiation. In contrast to 1,25(OH)2D3, these synthetic compds. did not demonstrate appreciable binding to serum vitamin D binding protein, a property that is correlated with fewer calcium effects in vivo. Two mimics tested in mice showed greater induction of a VDR target gene with less elevation of serum calcium than 1,25(OH)2D3. These novel VDR modulators may have potential as therapeutics for cancer, leukemia and psoriasis with less calcium mobilization side effects than are assocd. with secosteroidal 1,25(OH)2D3 analogs.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXjt1Oqs7c%253D&md5=6d86e9945e2051aee8c2efaf761c97e3

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    Kashiwagi, H. ; Ohta, M. ; Ono, Y. ; Morikami, K. ; Itoh, S. ; Sato, H. ; Takahashi, T. Effects of fluorines on nonsecosteroidal vitamin D receptor agonists. Bioorg. Med. Chem. 2013, 21 (3), 712– 721,  DOI: 10.1016/j.bmc.2012.11.029

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    Effects of fluorines on nonsecosteroidal vitamin D receptor agonists

    Kashiwagi, Hirotaka; Ohta, Masateru; Ono, Yoshiyuki; Morikami, Kenji; Itoh, Susumu; Sato, Hideki; Takahashi, Tadakatsu

    Bioorganic & Medicinal Chemistry (2013), 21 (3), 712-721CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)

    From our research of nonsecosteroidal vitamin D3 derivs. with gamma hydroxy carboxylic acid, we identified compd. 6, with two CF3 groups in the side chain, as a most potent vitamin D receptor (VDR) agonist that shows superagonistic activity in VDRE reporter gene assay, MG-63 osteocalcin prodn. assay and HL-60 cell differentiation assay. Compd. 6 demonstrated that fluorination is as effective in the case of our nonsecosteroidal scaffold as in the case of secosteroidal VD3 analogs. X-ray anal. of the VDR with compd. 6 revealed all of the six fluorine atoms of the hexafluoropropanol (HFP) moiety in the side chain effectively interacting with the VDR by both steric (van der Waals) and electrostatic (hydrogen bond, NH-F and CH-F) interactions. The HFP moiety of 6 effectively interacts with helix 12 (H12) of the VDR and stabilizes the position and the orientation of H12, which could result in stabilizing the coactivator and enhancing the VDR agonistic activity.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVOjsr7O&md5=d1b938056487ea729ec4b3d32195c3cf

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    Hao, M. ; Hou, S. ; Xue, L. ; Yuan, H. ; Zhu, L. ; Wang, C. ; Wang, B. ; Tang, C. ; Zhang, C. Further developments of the phenyl-pyrrolyl pentane series of nonsteroidal vitamin D receptor modulators as anticancer agents. J. Med. Chem. 2018, 61 (7), 3059– 3075,  DOI: 10.1021/acs.jmedchem.8b00106

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    81

    Further Developments of the Phenyl-Pyrrolyl Pentane Series of Nonsteroidal Vitamin D Receptor Modulators as Anticancer Agents

    Hao, Meixi; Hou, Siyuan; Xue, Lingjing; Yuan, Haoliang; Zhu, Lulu; Wang, Cong; Wang, Bin; Tang, Chunming; Zhang, Can

    Journal of Medicinal Chemistry (2018), 61 (7), 3059-3075CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    The vitamin D3 receptor (VDR), which belongs to the nuclear-receptor superfamily, is a potential mol. target for anticancer-drug discovery. In this study, a series of nonsteroidal vitamin D mimics with phenyl-pyrrolyl pentane skeletons with therapeutic potentials in cancer treatment were synthesized. Among them, 11b (N-(3-(diethylamino)propyl)-1-ethyl-5-(3-(4-((3-ethyl-3-hydroxypentyl)oxy)-3-methylphenyl)pentan-3-yl)-1H-pyrrole-2-carboxamide) and 11g (1-ethyl-5-{1-ethyl-1-[4-(3-ethyl-3-hydroxypentyloxy)-3-methylphenyl]propyl}-1H-pyrrole-2-carboxylic acid (3-morpholin-4-yl-propyl)amide) were identified as the most effective agents in reducing the viability of four cancer-cell lines, particularly those of breast-cancer cells, with IC50 values in the submicromolar-concn. range. In addn., 11b and 11g possessed VDR-binding affinities and displayed significant partial VDR-agonistic activities detd. by dual-luciferase-reporter assays and human-leukemia-cell-line (HL-60)-differentiation assays. Furthermore, 11b and 11g inhibited tumor growth in an orthotopic breast-tumor model via inhibition of cell proliferation and induction of cell apoptosis. More importantly, 11b and 11g exhibited favorable pharmacokinetic behavior in vivo and did not increase serum calcium levels or cause any other apparent side effects. In summary, 11b and 11g act as novel VDR modulators and may be promising candidates for cancer chemotherapy.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXktFWjurw%253D&md5=e61934d60110bc4da3942d086e397229

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    Shen, W. ; Xue, J. ; Zhao, Z. ; Zhang, C. Novel nonsecosteroidal VDR agonists with phenyl-pyrrolyl pentane skeleton. Eur. J. Med. Chem. 2013, 69 , 768– 778,  DOI: 10.1016/j.ejmech.2013.09.015

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    Novel nonsecosteroidal VDR agonists with phenyl-pyrrolyl pentane skeleton

    Shen, Wei; Xue, Jingwei; Zhao, Zekai; Zhang, Can

    European Journal of Medicinal Chemistry (2013), 69 (), 768-778CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)

    In order to find the vitamin D receptor (VDR) ligand whose VDR agonistic activity is sepd. from the calcemic activity sufficiently, novel nonsecosteroidal analogs with phenyl-pyrrolyl pentane skeleton were synthesized and evaluated for the VDR binding affinity, antiproliferative activity in vitro and serum calcium raising ability in vivo (tacalcitol used as control). Among them, several compds. showed varying degrees of VDR agonistic and growth inhibition activities of the tested cell lines. The most effective compd. 2g (EC50: 1.06 nM) exhibited stronger VDR agonistic activity than tacalcitol (EC50: 7.05 nM), inhibited the proliferations of HaCaT and MCF-7 cells with IC50 of 2.06 μM and 0.307 μM (tacalcitol: 2.07 μM and 0.057 μM) and showed no significant effect on serum calcium.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslaqs7vO&md5=5490cb28d0031e8b92211b9260dcfe6a

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    Gogoi, P. ; Seoane, S. ; Sigueiro, R. ; Guiberteau, T. ; Maestro, M. A. ; Perez-Fernandez, R. ; Rochel, N. ; Mouriño, A. Aromatic-based design of highly active and noncalcemic vitamin D receptor agonists. J. Med. Chem. 2018, 61 (11), 4928– 4937,  DOI: 10.1021/acs.jmedchem.8b00337

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    83

    Aromatic-Based Design of Highly Active and Noncalcemic Vitamin D Receptor Agonists

    Gogoi, Pranjal; Seoane, Samuel; Sigueiro, Rita; Guiberteau, Thierry; Maestro, Miguel A.; Perez-Fernandez, Roman; Rochel, Natacha; Mourino, Antonio

    Journal of Medicinal Chemistry (2018), 61 (11), 4928-4937CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    We report the design, synthesis, biol. evaluation, and structural anal. of a new class of vitamin D analogs that possess an arom. m-phenylene D-ring and an alkyl chain replacing the C-ring. A key feature of the synthetic strategy is a stereoselective Pd-catalyzed construction of the triene system in aq. medium that allows the rapid prepn. of small amts. of VDR ligands for biol. screening. Analogs with the shorter and longer side chains attached to the triene system have no calcemic activity. Compd. I binds to VDR with the same order of magnitude than calcipotriol and oxacalcitriol. It also reduces proliferation in normal and tumor cells similarly to the natural hormone 1α,25-dihydroxyvitamin D3, calcipotriol, and oxacalcitriol, suggesting preclin. studies related to hyperproliferative disorders such as psoriasis and cancer.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXptVWhsr4%253D&md5=19227221ee1974f5258c56cc47d26913

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    Gogoi, P. ; Sigueiro, R. ; Eduardo, S. ; Mouriño, A. An expeditious route to 1α,25-dihydroxyvitamin D3 and its analogues by an aqueous tandem palladium-catalyzed A-ring closure and suzuki coupling to the C/D unit. Chem. - Eur. J. 2010, 16 (5), 1432– 1435,  DOI: 10.1002/chem.200902972

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    An Expeditious Route to 1α,25-Dihydroxyvitamin D3 and Its Analogs by an Aqueous Tandem Palladium-Catalyzed A-Ring Closure and Suzuki Coupling to the C/D Unit

    Gogoi, Pranjal; Sigueeiro, Rita; Eduardo, Silvina; Mourino, Antonio

    Chemistry - A European Journal (2010), 16 (5), 1432-1435, S1432/1-S1432/55CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)

    A concise, general, and stereoselective entry to the vitamin D triene system of the natural hormone 1α,25-dihydroxyvitamin D3 and six representative analogs was achieved by an efficient strategy featuring a highly stereoselective intramol. cyclization of an enol triflate (A ring or lower fragment) followed in situ by a Suzuki-Miyaura coupling of the resulting palladium intermediate with an alkenylboronic ester (CD side chain upper fragment). The method employed equil-molar quantities of both fragments under protic conditions and can be used for the prepn. of small amts. of new vitamin D analogs for biol. testing. E.g., calcitriol analog I was prepd. with 78% yield by reacting boronic acid ester II (R25 = SiEt3) with 1,1,1-trifluoromethanesulfonic acid (2S,3S,4R)-2,4-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-methyl-1-methylene-6-heptyn-1-yl ester using (Ph3P)2PdCl2 and K3PO4 in THF followed by treatment of the resulting protected intermediate with TBAF in THF. Further synthetic studies pertaining to even more challenging vitamin D analogs are underway.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVKjsLw%253D&md5=2f6287aef8625fce2f73c4b1ba02a64b

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    Stio, M. ; Martinesi, M. ; Bruni, S. ; Treves, C. ; Mathieu, C. ; Verstuyf, A. ; d'Albasio, G. ; Bagnoli, S. ; Bonanomi, A. G. The vitamin D analogue TX 527 blocks NF-kappaB activation in peripheral blood mononuclear cells of patients with Crohn's disease. J. Steroid Biochem. Mol. Biol. 2007, 103 (1), 51– 60,  DOI: 10.1016/j.jsbmb.2006.07.008

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    The Vitamin D analogue TX 527 blocks NF-κB activation in peripheral blood mononuclear cells of patients with Crohn's disease

    Stio, Maria; Martinesi, Maria; Bruni, Sara; Treves, Cristina; Mathieu, Chantal; Verstuyf, Annemieke; d'Albasio, Giuseppe; Bagnoli, Siro; Bonanomi, Andrea G.

    Journal of Steroid Biochemistry and Molecular Biology (2007), 103 (1), 51-60CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier Ltd.)

    Crohn's disease (CD) is an inflammatory disease characterized by the activation of the immune system in the gut. Since tumor necrosis factor (TNF-α) plays an important role in the initiation and perpetuation of intestinal inflammation in CD, we investigated whether TX 527 [19-nor-14,20-bisepi-23-yne-1,25(OH)2D3], a Vitamin D analog, could affect peripheral blood mononuclear cells (PBMC) proliferation and exert an immunosuppressive effect on TNF-α prodn. in CD patients, and whether this immunosuppressive action could be mediated by NF-κB down-regulation. TX 527 significantly decreased cell proliferation and TNF-α levels. On activation, NF-κB, rapidly released from its cytoplasmic inhibitor (IKB-α), transmigrates into the nucleus and binds to DNA response elements in gene promoter regions. The activation of NF-κB, stimulated by TNF-α, and its nuclear translocation together with the degrdn. of IKB-α were blocked by TX 527. At the same time, NF-κB protein levels present in cytoplasmic exts. decreased in the presence of TNF-α and increased when PBMC were incubated with TX 527. The results of our studies indicate that TX 527 inhibits TNF-α mediated effects on PBMC and the activation of NF-κB and that its action is mediated by Vitamin D receptor (VDR), which is activated when the cells are stimulated with TX 527.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xht1OhtLzI&md5=443d99a6c2725bd7a85c4451ec35a011

  86. 86

    Sherman, M. H. ; Yu, R. T. ; Engle, D. D. ; Ding, N. ; Atkins, A. R. ; Tiriac, H. ; Collisson, E. A. ; Connor, F. ; Van Dyke, T. ; Kozlov, S. ; Martin, P. ; Tseng, T. W. ; Dawson, D. W. ; Donahue, T. R. ; Masamune, A. ; Shimosegawa, T. ; Apte, M. V. ; Wilson, J. S. ; Ng, B. ; Lau, S. L. ; Gunton, J. E. ; Wahl, G. M. ; Hunter, T. ; Drebin, J. A. ; O'Dwyer, P. J. ; Liddle, C. ; Tuveson, D. A. ; Downes, M. ; Evans, R. M. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 2014, 159 (1), 80– 93,  DOI: 10.1016/j.cell.2014.08.007

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    86

    Vitamin D Receptor-Mediated Stromal Reprogramming Suppresses Pancreatitis and Enhances Pancreatic Cancer Therapy

    Sherman, Mara H.; Yu, Ruth T.; Engle, Dannielle D.; Ding, Ning; Atkins, Annette R.; Tiriac, Herve; Collisson, Eric A.; Connor, Frances; Van Dyke, Terry; Kozlov, Serguei; Martin, Philip; Tseng, Tiffany W.; Dawson, David W.; Donahue, Timothy R.; Masamune, Atsushi; Shimosegawa, Tooru; Apte, Minoti V.; Wilson, Jeremy S.; Ng, Beverly; Lau, Sue Lynn; Gunton, Jenny E.; Wahl, Geoffrey M.; Hunter, Tony; Drebin, Jeffrey A.; O'Dwyer, Peter J.; Liddle, Christopher; Tuveson, David A.; Downes, Michael; Evans, Ronald M.

    Cell (Cambridge, MA, United States) (2014), 159 (1), 80-93CODEN: CELLB5; ISSN:0092-8674. (Cell Press)

    The poor clin. outcome in pancreatic ductal adenocarcinoma (PDA) is attributed to intrinsic chemoresistance and a growth-permissive tumor microenvironment. Conversion of quiescent to activated pancreatic stellate cells (PSCs) drives the severe stromal reaction that characterizes PDA. Here, we reveal that the vitamin D receptor (VDR) is expressed in stroma from human pancreatic tumors and that treatment with the VDR ligand calcipotriol markedly reduced markers of inflammation and fibrosis in pancreatitis and human tumor stroma. We show that VDR acts as a master transcriptional regulator of PSCs to reprise the quiescent state, resulting in induced stromal remodeling, increased intratumoral gemcitabine, reduced tumor vol., and a 57% increase in survival compared to chemotherapy alone. This work describes a mol. strategy through which transcriptional reprogramming of tumor stroma enables chemotherapeutic response and suggests vitamin D priming as an adjunct in PDA therapy.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1GmtLfO&md5=126f51933053c27e76f247760f71bb99

  87. 87

    Carlberg, C. Genome-wide (over)view on the actions of vitamin D. Front. Physiol. 2014, 5 , 167,  DOI: 10.3389/fphys.2014.00167

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    87

    Genome-wide (over)view on the actions of vitamin D

    Carlberg Carsten

    Frontiers in physiology (2014), 5 (), 167 ISSN:1664-042X.

    For a global understanding of the physiological impact of the nuclear hormone 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) the analysis of the genome-wide locations of its high affinity receptor, the transcription factor vitamin D receptor (VDR), is essential. Chromatin immunoprecipitation sequencing (ChIP-seq) in GM10855 and GM10861 lymphoblastoid cells, undifferentiated and lipopolysaccharide-differentiated THP-1 monocytes, LS180 colorectal cancer cells and LX2 hepatic stellate cells revealed between 1000 and 13,000 VDR-specific genomic binding sites. The harmonized analysis of these ChIP-seq datasets indicates that the mechanistic basis for the action of the VDR is independent of the cell type. Formaldehyde-assisted isolation of regulatory elements sequencing (FAIRE-seq) data highlight accessible chromatin regions, which are under control of 1,25(OH)2D3. In addition, public data, such as from the ENCODE project, allow to relate the genome-wide actions of VDR and 1,25(OH)2D3 to those of other proteins within the nucleus. For example, locations of the insulator protein CTCF suggest a segregation of the human genome into chromatin domains, of which more than 1000 contain at least one VDR binding site. The integration of all these genome-wide data facilitates the identification of the most important VDR binding sites and associated primary 1,25(OH)2D3 target genes. Expression changes of these key genes can serve as biomarkers for the actions of vitamin D3 and its metabolites in different tissues and cell types of human individuals. Analysis of primary tissues obtained from vitamin D3 intervention studies using such markers indicated a large inter-individual variation for the efficiency of vitamin D3 supplementation. In conclusion, a genome-wide (over)view on the genomic locations of VDR provides a broader basis for addressing vitamin D's role in health and disease.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cflvVOltw%253D%253D&md5=0f009ced1e403d9e0167814849afbec2

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    Plum, L. A. ; DeLuca, H. F. Vitamin D, disease and therapeutic opportunities. Nat. Rev. Drug Discovery 2010, 9 (12), 941– 955,  DOI: 10.1038/nrd3318

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    88

    Vitamin D, disease and therapeutic opportunities

    Plum, Lori A.; DeLuca, Hector F.

    Nature Reviews Drug Discovery (2010), 9 (12), 941-955CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)

    A review. The discovery of the vitamin D endocrine system and a receptor for the hormonal form, 1α,25-dihydroxyvitamin D3, has brought a new understanding of the relationship between vitamin D and metabolic bone diseases, and has also established the functions of vitamin D beyond the skeleton. This has ushered in many investigations into the possible roles of vitamin D in autoimmune diseases, cardiovascular disorders, infectious diseases, cancers and granuloma-forming diseases. This article presents an evaluation of the possible roles of vitamin D in these diseases. The potential of vitamin D-based therapies in treating diseases for which the evidence is most compelling is also discussed.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsV2ju77L&md5=80e3b525fc102701a5360db8724c4fc7

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    Leyssens, C. ; Verlinden, L. ; Verstuyf, A. The future of vitamin D analogs. Front. Physiol. 2014, 5 , 122,  DOI: 10.3389/fphys.2014.00122

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    89

    The future of vitamin D analogs

    Leyssens Carlien; Verlinden Lieve; Verstuyf Annemieke

    Frontiers in physiology (2014), 5 (), 122 ISSN:1664-042X.

    The active form of vitamin D3, 1,25-dihydroxyvitamin D3, is a major regulator of bone and calcium homeostasis. In addition, this hormone also inhibits the proliferation and stimulates the differentiation of normal as well as malignant cells. Supraphysiological doses of 1,25-dihydroxyvitamin D3 are required to reduce cancer cell proliferation. However, these doses will lead in vivo to calcemic side effects such as hypercalcemia and hypercalciuria. During the last 25 years, many structural analogs of 1,25-dihydroxyvitamin D3 have been synthesized by the introduction of chemical modifications in the A-ring, central CD-ring region or side chain of 1,25-dihydroxyvitamin D3 in the hope to find molecules with a clear dissociation between the beneficial antiproliferative effects and adverse calcemic side effects. One example of such an analog with a good dissociation ratio is calcipotriol (Daivonex®), which is clinically used to treat the hyperproliferative skin disease psoriasis. Other vitamin D analogs were clinically approved for the treatment of osteoporosis or secondary hyperparathyroidism. No vitamin D analog is currently used in the clinic for the treatment of cancer although several analogs have been shown to be potent drugs in animal models of cancer. Transcriptomics studies as well as in vitro cell biological experiments unraveled basic mechanisms involved in the antineoplastic effects of vitamin D and its analogs. 1,25-dihydroxyvitamin D3 and analogs act in a cell type- and tissue-specific manner. Moreover, a blockade in the transition of the G0/1 toward S phase of the cell cycle, induction of apoptosis, inhibition of migration and invasion of tumor cells together with effects on angiogenesis and inflammation have been implicated in the pleiotropic effects of 1,25-dihydroxyvitamin D3 and its analogs. In this review we will give an overview of the action of vitamin D analogs in tumor cells and look forward how these compounds could be introduced in the clinical practice.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cflvVartA%253D%253D&md5=eff34071756c8f181160ca229b5dc512

  90. 90

    Tocchini-Valentini, G. ; Rochel, N. ; Wurtz, J. M. ; Mitschler, A. ; Moras, D. Crystal structures of the vitamin D receptor complexed to superagonist 20-epi ligands. Proc. Natl. Acad. Sci. U. S. A. 2001, 98 (10), 5491– 5496,  DOI: 10.1073/pnas.091018698

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    90

    Crystal structures of the vitamin D receptor complexed to superagonist 20-epi ligands

    Tocchini-Valentini, G.; Rochel, N.; Wurtz, J. M.; Mitschler, A.; Moras, D.

    Proceedings of the National Academy of Sciences of the United States of America (2001), 98 (10), 5491-5496CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

    The crystal structures of the ligand-binding domain (LBD) of the vitamin D receptor complexed to 1α,25(OH)2D3 and the 20-epi analogs, MC1288 and KH1060, show that the protein conformation is identical, conferring a general character to the observation first made for retinoic acid receptor (RAR) that, for a given LBD, the agonist conformation is unique, the ligands adapting to the binding pocket. In all complexes, the A- to D-ring moieties of the ligands adopt the same conformation and form identical contacts with the protein. Differences are obsd. only for the 17β-aliph. chains that adapt their conformation to anchor the 25-hydroxyl group to His 305 and His 397. The inverted geometry of the C20 Me group induces different paths of the aliph. chains. The ligands exhibit a low-energy conformation for MC1288 and a more strained conformation for the two others. KH1060 compensates this energy cost by addnl. contacts. Based on the present data, the explanation of the superagonist effect is to be found in higher stability and longer half-life of the active complex, thereby excluding different conformations of the ligand binding domain.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXjs1Wgu74%253D&md5=942bd4ff70ff474b4f59998afabda39b

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    Tocchini-Valentini, G. ; Rochel, N. ; Wurtz, J. M. ; Moras, D. Crystal structures of the vitamin D nuclear receptor liganded with the vitamin D side chain analogues calcipotriol and seocalcitol, receptor agonists of clinical importance: insights into a structural basis for the switching of calcipotriol to a receptor antagonist by further side chain modification. J. Med. Chem. 2004, 47 (8), 1956– 1961,  DOI: 10.1021/jm0310582

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    91

    Crystal Structures of the Vitamin D Nuclear Receptor Liganded with the Vitamin D Side Chain Analogues Calcipotriol and Seocalcitol, Receptor Agonists of Clinical Importance. Insights into a Structural Basis for the Switching of Calcipotriol to a Receptor Antagonist by Further Side Chain Modification

    Tocchini-Valentini, Giuseppe; Rochel, Natacha; Wurtz, Jean-Marie; Moras, Dino

    Journal of Medicinal Chemistry (2004), 47 (8), 1956-1961CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    The plethora of actions of 1α,25(OH)2D3 in various systems suggested wide clin. applications of vitamin D nuclear receptor (VDR) ligands in treatments of inflammation, dermatol. indication, osteoporosis, cancers, and autoimmune diseases. More than 3000 vitamin D analogs have been synthesized in order to reduce the calcemic side effects while maintaining the transactivation potency of these ligands. Here, we report the crystal structures of VDR ligand binding domain bound to two vitamin D agonists of therapeutical interest, calcipotriol and seocalcitol, which are characterized by their side chain modifications. These structures show the conservation of the VDR structure and the adaptation of the side chain anchored by hydroxyl moieties. The structure of VDR-calcipotriol helps us to understand the structural basis for the switching of calcipotriol to a receptor antagonist by further side chain modification. The VDR-seocalcitol structure, in comparison with the structure of VDR-KH1060, a superagonist ligand closely related to seocalcitol, shows adaptation of the D ring and position of C-21 in order to adapt its more rigid side chain.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXitValsLk%253D&md5=8a30a7bfca5475f48e2a1583915ec494

  92. 92

    Eelen, G. ; Verlinden, L. ; Rochel, N. ; Claessens, F. ; De Clercq, P. ; Vandewalle, M. ; Tocchini-Valentini, G. ; Moras, D. ; Bouillon, R. ; Verstuyf, A. Superagonistic action of 14-epi-analogs of 1,25-dihydroxyvitamin D explained by vitamin D receptor-coactivator interaction. Mol. Pharmacol. 2005, 67 (5), 1566– 1573,  DOI: 10.1124/mol.104.008730

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    92

    Superagonistic action of 14-epi-analogs of 1,25-dihydroxyvitamin D explained by vitamin D receptor-coactivator interaction

    Eelen, Guy; Verlinden, Lieve; Rochel, Natacha; Claessens, Frank; De Clercq, Pierre; Vandewalle, Maurits; Tocchini-Valentini, Giuseppe; Moras, Dino; Bouillon, Roger; Verstuyf, Annemieke

    Molecular Pharmacology (2005), 67 (5), 1566-1573CODEN: MOPMA3; ISSN:0026-895X. (American Society for Pharmacology and Experimental Therapeutics)

    Two 14-epi-analogs of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], 19-nor-14-epi-23-yne-1,25-(OH)2D3 (TX 522) and 19-nor-14,20-bisepi-23-yne-1,25-(OH)2D3 (TX 527), show enhanced antiproliferative (at least 10-fold) and markedly lower calcemic effects both in vitro and in vivo, compared with 1,25-(OH)2D3. This study aimed to evaluate their superagonistic effect at the level of interaction between the Vitamin D receptor (VDR) and coactivators. Mammalian two-hybrid assays with VP16-fused VDR and GAL4-DNA-binding-domain-fused steroid receptor coactivator 1 (SRC-1), transcriptional intermediary factor 2 (Tif2), or DRIP205 showed the 14-epi-analogs to be more potent inducers of VDR-coactivator interactions than 1,25-(OH)2D3 (up to 16- and 20-fold stronger induction of VDR-SRC-1 interaction for TX 522 and TX 527 at 10-10 M). Similar assays in which metab. of 1,25-(OH)2D3 was blocked with VID 400, a selective inhibitor of the 1,25-(OH)2D3-metabolizing enzyme CYP24, showed that the enhanced potency of these analogs in establishing VDR-coactivator interactions can only partially be accounted for by their increased resistance to metabolic degrdn. Crystn. of TX 522 complexed to the ligand binding domain of the human VDR demonstrated that the epi-configuration of C14 caused the CD ring of the ligand to shift by 0.5 Ã…, thereby bringing the C12 atom into closer contact with Val300. Moreover, C22 of TX 522 made an addnl. contact with the CD1 atom of Ile268 because of the rigidity of the triple bond-contg. side chain. The position and conformation of the activation helix H12 of VDR was strictly maintained. In conclusion, this study provides deeper insight into the docking of TX 522 in the LBP and shows that stronger VDR-coactivator interactions underlie the superagonistic activity of the two 14-epi-analogs.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXktFegtro%253D&md5=82b77bd5efdf876ac49a84b0357215ad

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    Hourai, S. ; Fujishima, T. ; Kittaka, A. ; Suhara, Y. ; Takayama, H. ; Rochel, N. ; Moras, D. Probing a water channel near the A-ring of receptor-bound 1α,25-dihydroxyvitamin D3 with selected 2α-substituted analogues. J. Med. Chem. 2006, 49 , 5199– 5205,  DOI: 10.1021/jm0604070

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    93

    Probing a Water Channel near the A-Ring of Receptor-Bound 1α,25-Dihydroxyvitamin D3 with Selected 2α-Substituted Analogues

    Hourai, Shinji; Fujishima, Toshie; Kittaka, Atsushi; Suhara, Yoshitomo; Takayama, Hiroaki; Rochel, Natacha; Moras, Dino

    Journal of Medicinal Chemistry (2006), 49 (17), 5199-5205CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    The crystal structure of the vitamin D receptor (VDR) in complex with 1α,25(OH)2D3 revealed the presence of several water mols. near the A-ring linking the ligand C-2 position to the protein surface. Here, we report the crystal structures of the human VDR ligand binding domain bound to selected C-2α substituted analogs, namely, Me, Pr, propoxy, hydroxypropyl, and hydroxypropoxy. These specific replacements do not modify the structure of the protein or the ligand, but with the exception of the Me substituent, all analogs affect the presence and/or the location of the above water mols. The integrity of the channel interactions and specific C-2α analog directed addnl. interactions correlate with the binding affinity of the ligands. In contrast, the resulting loss or gain of H-bonds does not reflect the magnitude of HL60 cell differentiation. Our overall findings highlight a rational approach to the design of more potent ligands by building in features revealed in the crystal structures.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xns1WqsLw%253D&md5=3d01ee279730837fbc38fae276a066fd

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    Kakuda, S. ; Ishizuka, S. ; Eguchi, H. ; Mizwicki, M. T. ; Norman, A. W. ; Takimoto-Kamimura, M. Structural basis of the histidine-mediated vitamin D receptor agonistic and antagonistic mechanisms of (23S)-25-dehydro-1α-hydroxyvitamin D3-26,23-lactone. Acta Crystallogr., Sect. D: Biol. Crystallogr. 2010, 66 (Part 8), 918– 926,  DOI: 10.1107/S0907444910020810

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    94

    Structural basis of the histidine-mediated vitamin D receptor agonistic and antagonistic mechanisms of (23S)-25-dehydro-1α-hydroxyvitamin D3-26,23-lactone

    Kakuda, Shinji; Ishizuka, Seiichi; Eguchi, Hiroshi; Mizwicki, Mathew T.; Norman, Anthony W.; Takimoto-Kamimura, Midori

    Acta Crystallographica, Section D: Biological Crystallography (2010), 66 (8), 918-926CODEN: ABCRE6; ISSN:0907-4449. (International Union of Crystallography)

    TEI-9647 antagonizes vitamin D receptor (VDR) mediated genomic actions of 1α,25(OH)2D3 in human cells but is agonistic in rodent cells. The presence of Cys403, Cys410 or of both residues in the C-terminal region of human VDR (hVDR) results in antagonistic action of this compd. In the complexes of TEI-9647 with wild-type hVDR (hVDRwt) and H397F hVDR, TEI-9647 functions as an antagonist and forms a covalent adduct with hVDR according to MALDI-TOF MS. The crystal structures of complexes of TEI-9647 with rat VDR (rVDR), H305F hVDR and H305F/H397F hVDR showed that the agonistic activity of TEI-9647 is caused by a hydrogen-bond interaction with His397 or Phe397 located in helix 11. Both biol. activity assays and the crystal structure of H305F hVDR complexed with TEI-9647 showed that the interaction between His305 and TEI-9647 is crucial for antagonist activity. This study indicates the following stepwise mechanism for TEI-9647 antagonism. Firstly, TEI-9647 forms hydrogen bonds to His305, which promote conformational changes in hVDR and draw Cys403 or Cys410 towards the ligand. This is followed by the formation of a 1,4-Michael addn. adduct between the thiol (-SH) group of Cys403 or Cys410 and the exo-methylene group of TEI-9647.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXpvVSlsbs%253D&md5=d475359d036b2be2abf7950308fddc4a

  95. 95

    Antony, P. ; Sigüeiro, R. ; Huet, T. ; Sato, Y. ; Ramalanjaona, N. ; Rodrigues, L. C. ; Mouriño, A. ; Moras, D. ; Rochel, N. Structure-function relationships and crystal structures of the vitamin D receptor bound 2α-methyl-(20S,23S)- and 2α-methyl-(20S,23R)-epoxymethano-1α,25-dihydroxyvitamin D3 . J. Med. Chem. 2010, 53 (3), 1159– 1171,  DOI: 10.1021/jm9014636

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    95

    Structure-Function Relationships and Crystal Structures of the Vitamin D Receptor Bound 2α-Methyl-(20S,23S)- and 2α-Methyl-(20S,23R)-epoxymethano-1α,25-dihydroxyvitamin D3

    Antony, Pierre; Siguiro, Rita; Huet, Tiphaine; Sato, Yoshiteru; Ramalanjaona, Nick; Rodrigues, Luis Cezar; Mourino, Antonio; Moras, Dino; Rochel, Natacha

    Journal of Medicinal Chemistry (2010), 53 (3), 1159-1171CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    The vitamin D nuclear receptor is a ligand-dependent transcription factor that controls multiple biol. responses such as cell proliferation, immune responses, and bone mineralization. Numerous 1α,25(OH)2D3 analogs, which exhibit low calcemic side effects and/or antitumoral properties, have been synthesized. The authors recently showed that the synthetic analog (20S,23S)-epoxymethano-1α,25-dihydroxyvitamin D3 acts as a 1α,25(OH)2D3 superagonist and exhibits both antiproliferative and prodifferentiating properties in vitro. Using this information and on the basis of the crystal structures of human VDR ligand binding domain (hVDR LBD) bound to 1α,25(OH)2D3, 2α-methyl-1α,25(OH)2D3, or (20S,23S)-epoxymethano-1α,25-dihydroxyvitamin D3, the authors designed a novel analog, 2α-methyl-(20S,23S)-epoxymethano-1α,25-dihydroxyvitamin D3, to increase its transactivation potency. Here, the authors solved the crystal structures of the hVDR LBD in complex with 2α-methyl-(20S,23S)-epoxymethano-1α,25-dihydroxyvitamin D3 (C23S) and its epimer (C23R) and detd. their correlation with specific biol. outcomes.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXkvFCrsw%253D%253D&md5=04b4c3fb4cdd30d346a8fe4be8ee824b

  96. 96

    Molnár, F. ; Sigüeiro, R. ; Sato, Y. ; Araujo, C. ; Schuster, I. ; Antony, P. ; Peluso, J. ; Muller, C. ; Mouriño, A. ; Moras, D. ; Rochel, N. 1α,25(OH)2-3-epi-vitamin D3, a natural physiological metabolite of vitamin D3: its synthesis, biological activity and crystal structure with its receptor. PLoS One 2011, 6 , e18124,  DOI: 10.1371/journal.pone.0018124

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    96

    1α,25(OH)2-3-epi-Vitamin D3, a natural physiological metabolite of vitamin D3: its synthesis, biological activity and crystal structure with its receptor

    Molnar, Ferdinand; Sigueiro, Rita; Sato, Yoshiteru; Araujo, Clarisse; Schuster, Inge; Antony, Pierre; Peluso, Jean; Muller, Christian; Mourino, Antonio; Moras, Dino; Rochel, Natacha

    PLoS One (2011), 6 (3), e18124CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)

    The 1α,25-dihydroxy-3-epi-vitamin-D3 (1α,25(OH)2-3-epi-D3) (I), a natural metabolite of the seco-steroid vitamin D3, exerts its biol. activity through binding to its cognate vitamin D nuclear receptor (VDR), a ligand dependent transcription regulator. In vivo action of I is tissue-specific and exhibits lowest calcemic effect compared to that induced by 1α,25(OH)2D3. To further unveil the structural mechanism and structure-activity relationships of I and its receptor complex, we characterized some of its in vitro biol. properties and solved its crystal structure complexed with human VDR ligand-binding domain (LBD). In the present study, we report the more effective synthesis with fewer steps that provides higher yield of the 3-epimer of the 1α,25(OH)2D3. We solved the crystal structure of its complex with the human VDR-LBD and found that this natural metabolite displays specific adaptation of the ligand-binding pocket, as the 3-epimer maintains the no. of hydrogen bonds by an alternative water-mediated interaction to compensate the abolished interaction with Ser278. In addn., the biol. activity of I in primary human keratinocytes and biochem. properties are comparable to 1α,25(OH)2D3. The physiol. role of this pathway as the specific biol. action of the 3-epimer remains unclear. However, its high metabolic stability together with its significant biol. activity makes this natural metabolite an interesting ligand for clin. applications. Our new findings contribute to a better understanding at mol. level how natural metabolites of 1α,25(OH)2D3 lead to significant activity in biol. systems and we conclude that the C3-epimerization pathway produces an active metabolite with similar biochem. and biol. properties to those of the 1α,25(OH)2D3.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXkslygu78%253D&md5=952308928998431a32fde8eae71b76ee

  97. 97

    Shindo, K. ; Kumagai, G. ; Takano, M. ; Sawada, D. ; Saito, N. ; Saito, H. ; Kakuda, S. ; Takagi, K. ; Ochiai, E. ; Horie, K. ; Takimoto-Kamimura, M. ; Ishizuka, S. ; Takenouchi, K. ; Kittaka, A. New C15-substituted active vitamin D3 . Org. Lett. 2011, 13 , 2852– 2855,  DOI: 10.1021/ol200828s

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    New C15-Substituted Active Vitamin D3

    Shindo, Kanako; Kumagai, Go; Takano, Masashi; Sawada, Daisuke; Saito, Nozomi; Saito, Hiroshi; Kakuda, Shinji; Takagi, Ken-ichiro; Ochiai, Eiji; Horie, Kyohei; Takimoto-Kamimura, Midori; Ishizuka, Seiichi; Takenouchi, Kazuya; Kittaka, Atsushi

    Organic Letters (2011), 13 (11), 2852-2855CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)

    C15-Substituted 1α,25-dihydroxyvitamin D3 analogs were synthesized for the first time to investigate the effects of the modified CD-ring on biol. activity concerning the agonistic positioning of helix-3 and helix-12 of the vitamin D receptor (VDR). X-ray cocrystallog. anal. proved that 0.6 Å shifts of the CD-ring and shrinking of the side chain were necessary to maintain the position of the 25-hydroxy group for proper interaction with helix-12. The 15-hydroxy-16-ene deriv. showed higher binding affinity for hVDR than the natural hormone.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXlsVyhs78%253D&md5=54b990ef426e47cb1249c464649e58b9

  98. 98

    Kashiwagi, H. ; Ono, Y. ; Shimizu, K. ; Haneishi, T. ; Ito, S. ; Iijima, S. ; Kobayashi, T. ; Ichikawa, F. ; Harada, S. ; Sato, H. ; Sekiguchi, N. ; Ishigai, M. ; Takahashi, T. Novel nonsecosteroidal vitamin D3 carboxylic acid analogs for osteoporosis, and SAR analysis. Bioorg. Med. Chem. 2011, 19 (16), 4721– 4729,  DOI: 10.1016/j.bmc.2011.07.001

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    98

    Novel nonsecosteroidal vitamin D3 carboxylic acid analogs for osteoporosis, and SAR analysis

    Kashiwagi, Hirotaka; Ono, Yoshiyuki; Shimizu, Kazuki; Haneishi, Tsuyoshi; Ito, Susumu; Iijima, Shigeyuki; Kobayashi, Takamitsu; Ichikawa, Fumihiko; Harada, Suguru; Sato, Hideki; Sekiguchi, Nobuo; Ishigai, Masaki; Takahashi, Tadakatsu

    Bioorganic & Medicinal Chemistry (2011), 19 (16), 4721-4729CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)

    Novel vitamin D3 analogs with carboxylic acid were explored, focusing on a nonsecosteroidal analog, LG190178, with a bisphenyl skeleton. From X-ray anal. of these analogs with vitamin D receptor (VDR), the carboxyl groups had very unique hydrogen bonding interactions in VDR and mimicked 1α-hydroxy group and/or 3β-hydroxy group of 1α,25-dihydroxyvitamin D3. A highly potent analog, 6a (I), with good in vitro activity and pharmacokinetic profiles was identified from an SAR study. Compd. 6a showed significant prevention of bone loss in a rat osteoporosis model by oral administration.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXpvFWitLo%253D&md5=09e6b50f1eaef8db568119e0c178c900

  99. 99

    Hourai, S. ; Rodrigues, L. ; Antony, P. ; Reina-San-Martin, B. ; Ciesielski, F. ; Magnier, B. ; Schoonjans, K. ; Mouriño, A. ; Rochel, N. ; Moras, D. Structure-based design of a superagonist ligand for the vitamin D nuclear receptor. Chem. Biol. 2008, 15 , 383– 392,  DOI: 10.1016/j.chembiol.2008.03.016

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    99

    Structure-Based Design of a Superagonist Ligand for the Vitamin D Nuclear Receptor

    Hourai, Shinji; Rodrigues, Luis Cezar; Antony, Pierre; Reina-San-Martin, Bernardo; Ciesielski, Fabrice; Magnier, Benjamin Claude; Schoonjans, Kristina; Mourino, Antonio; Rochel, Natacha; Moras, Dino

    Chemistry & Biology (Cambridge, MA, United States) (2008), 15 (4), 383-392CODEN: CBOLE2; ISSN:1074-5521. (Cell Press)

    Summary: Vitamin D nuclear receptor (VDR), a ligand-dependent transcriptional regulator, is an important target for multiple clin. applications, such as osteoporosis and cancer. Since exacerbated increase of calcium serum level is currently assocd. with VDR ligands action, superagonists with low calcium serum levels have been developed. Based on the crystal structures of human VDR (hVDR) bound to 1α,25-dihydroxyvitamin D3 and superagonists-notably, KH1060-we designed a superagonist ligand. To optimize the aliph. side chain conformation with a subsequent entropy benefit, we incorporated an oxolane ring and generated two stereo diastereomers, AMCR277A and AMCR277B. Only AMCR277A exhibits superagonist activity in vitro, but is as calcemic in vivo as the natural ligand. The crystal structures of the complexes between the ligand binding domain of hVDR and these ligands provide a rational approach to the design of more potent superagonist ligands for potential clin. application.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXkvFWqt7Y%253D&md5=7a4c4e081ec43665419542956191b1e8

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    Rochel, N. ; Moras, D. Crystal structure of a vitamin D3 analog, ZK203278, showing dissociated profile. Anticancer Res. 2012, 32 (1), 335– 339

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    100

    Crystal structure of a vitamin D3 analog, ZK203278, showing dissociated profile

    Rochel, Natacha; Moras, Dino

    Anticancer Research (2012), 32 (1), 335-340CODEN: ANTRD4; ISSN:0250-7005. (International Institute of Anticancer Research)

    The plethora of actions of 1α,25-dihydroxyvitamin D3, the active form of the seco-steroid hormone vitamin D, in various systems suggested wide clin. applications in treatments for renal osteodystrophy, osteoporosis, psoriasis, cancer, autoimmune diseases and prevention of graft rejection. However, the major side-effects of hypercalcemia of VDR ligands limit their use. ZK203278, a novel synthetic analog has been shown to act as a potent immunomodulator and presents dissocd. biol. profile with low calcemic side-effects. Here, we described the crystal structures of the hVDR ligand-binding domain in complex with ZK203278 and detd. its correlation with its specific dissocd. biol. profile. The VDR/ZK203278 structure, in comparison with VDR/1α,25-dihydroxyvitamin D3, shows specific interactions of the thiazole group of ZK203278 with residues of H3, H11 and H12. These specific interactions may lead to altered selective interactions with co-regulators and consequently to the dissocd. biol. profile of this novel ligand.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XitVWnsrs%253D&md5=2dabdf69ec22dd09492dac2e99764ffc

  101. 101

    Rochel, N. ; Hourai, S. ; Moras, D. Crystal structure of hereditary vitamin D-resistant rickets--associated mutant H305Q of vitamin D nuclear receptor bound to its natural ligand. J. Steroid Biochem. Mol. Biol. 2010, 121 , 84– 87,  DOI: 10.1016/j.jsbmb.2010.04.008

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    101

    Crystal structure of hereditary vitamin D-resistant rickets-Associated mutant H305Q of vitamin D nuclear receptor bound to its natural ligand

    Rochel, Natacha; Hourai, Shinji; Moras, Dino

    Journal of Steroid Biochemistry and Molecular Biology (2010), 121 (1-2), 84-87CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier Ltd.)

    In the nuclear receptor of vitamin D (VDR), histidine 305 participates in the anchoring of the ligand. The VDR H305Q mutation was identified in a patient who exhibited hereditary vitamin D-resistant rickets (HVDRR). We report the crystal structure of human VDR H305Q-ligand binding domain bound to 1α,25(OH)2D3 solved at 1.8 Å resoln. The protein adopts the active conformation of the wild-type liganded VDR. A local conformational flexibility at the mutation site weakens the hydrogen bond between the 25-OH with Gln305, thus explaining the lower affinity of the mutant proteins for calcitriol. The structure provides the basis for a rational approach to the design of more potent ligands for the treatment of HVDRR.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXptVGjt7Y%253D&md5=a5d6f89bf135b8e3a02d8e3af896d848

  102. 102

    Verlinden, L. ; Verstuyf, A. ; Eelen, G. ; Bouillon, R. ; Ordóñez-Morán, P. ; Larriba, M. J. ; Muñoz, A. ; Rochel, N. ; Sato, Y. ; Moras, D. ; Maestro, M. ; Seoane, S. ; Dominguez, F. ; Eduardo-Canosa, S. ; Nicoletti, D. ; Moman, E. ; Mouriño, A. Synthesis, structure, and biological activity of des-side chain analogues of 1α,25-dihydroxyvitamin D3 with substituents at C18. ChemMedChem 2011, 6 (5), 788– 793,  DOI: 10.1002/cmdc.201100021

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    102

    Synthesis, Structure, and Biological Activity of des-Side Chain Analogues of 1α,25-Dihydroxyvitamin D3 with Substituents at C18

    Verlinden, Lieve; Verstuyf, Annemieke; Eelen, Guy; Bouillon, Roger; Ordonez-Moran, Paloma; Larriba, Maria Jesus; Munoz, Alberto; Rochel, Natacha; Sato, Yoshiteru; Moras, Dino; Maestro, Miguel; Seoane, Samuel; Dominguez, Fernando; Eduardo-Canosa, Silvina; Nicoletti, Daniel; Moman, Edelmiro; Mourino, Antonio

    ChemMedChem (2011), 6 (5), 788-793CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)

    An improved synthetic route to 1α,25-dihydroxyvitamin D3 des-side chain analogs I [n = 4 (II),5] with substituents at C18 is reported, along with their biol. activity. These analogs display significant antiproliferative effects toward MCF-7 breast cancer cells and prodifferentiation activity toward SW480-ADH colon cancer cells; they are also characterized by a greatly decreased calcemic profile. The crystal structure of the human vitamin D receptor (hVDR) complexed to II reveals that the side chain introduced at position C18 adopts the same orientation in the ligand binding pocket as the side chain of 1α,25-dihydroxyvitamin D3.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXkvFGisL8%253D&md5=8144eaf8f79c51aa51d15da9f13e845b

  103. 103

    Fraga, R. ; Zacconi, F. ; Sussman, F. ; Ordonez-Moran, P. ; Muñoz, A. ; Huet, T. ; Molnár, F. ; Moras, D. ; Rochel, N. ; Maestro, M. ; Mouriño, A. Design, synthesis, evaluation, and structure of vitamin D analogues with furan side chains. Chem. - Eur. J. 2012, 18 (2), 603– 612,  DOI: 10.1002/chem.201102695

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    103

    Design, Synthesis, Evaluation, and Structure of Vitamin D Analogues with Furan Side Chains

    Fraga, Ramon; Zacconi, Flavia; Sussman, Fredy; Ordonez-Moran, Paloma; Munoz, Alberto; Huet, Tiphaine; Molnar, Ferdinand; Moras, Dino; Rochel, Natacha; Maestro, Miguel; Mourino, Antonio

    Chemistry - A European Journal (2012), 18 (2), 603-612, S603/1-S603/58CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)

    Based on the crystal structures of human vitamin D receptor (hVDR) bound to 1α,25-dihydroxy-vitamin D3 (1,25 D) and superagonist ligands, we previously designed new superagonist ligands with a THF ring at the side chain that optimize the aliph. side-chain conformation through an entropy benefit. Following a similar strategy, four novel vitamin D analogs with arom. furan side chains (e.g. I) have now been developed. The triene system has been constructed by an efficient stereoselective intramol. cyclization of an enol triflate (A-ring precursor) followed by a Suzuki-Miyaura coupling of the resulting intermediate with an alkenyl boronic ester (CD-side chain, upper fragment). The furan side chains have been constructed by gold chem. These analogs exhibit significant pro-differentiation effects and transactivation potency. The crystal structure of I in a complex with the ligand-binding domain of hVDR revealed that the side-chain furanic ring adopts two conformations.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsF2lurnE&md5=04236306f3d3c88b9660f00c83cf26dd

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    Saitoh, H. ; Chida, T. ; Takagi, K. ; Horie, K. ; Sawai, Y. ; Nakamura, Y. ; Harada, Y. ; Takenouchi, K. ; Kittaka, A. Synthesis of C-2 substituted vitamin D derivatives having ringed side chains and their biological evaluation, especially biological effect on bone by modification at the C-2 position. Org. Biomol. Chem. 2011, 9 (10), 3954– 3964,  DOI: 10.1039/c1ob05142c

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    104

    Synthesis of C-2 substituted vitamin D derivatives having ringed side chains and their biological evaluation, especially biological effect on bone by modification at the C-2 position

    Saitoh, Hiroshi; Chida, Takayuki; Takagi, Kenichiro; Horie, Kyohei; Sawai, Yoshiyuki; Nakamura, Yuko; Harada, Yoshifumi; Takenouchi, Kazuya; Kittaka, Atsushi

    Organic & Biomolecular Chemistry (2011), 9 (10), 3954-3964CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)

    To obtain vitamin D derivs., which have strong activity for enhancing bone growth, we designed vitamin D derivs. with various substitutions at the C-2 position. Novel 2 α-substituted vitamin D derivs. were synthesized starting from d-glucose as a chiral template of the A-ring with a CD-ring bromoolefin unit using the Trost coupling method. We evaluated these compds. by two in vitro assays, affinity to VDR and transactivation assays, using human osteosarcoma (Hos) cells, and demonstrated the SAR of the C-2 position of VD3. Furthermore, by using the OVX model, we found that compd. 5c, which has a hydroxypropoxy side chain at C-2 and 2,2-di-Me cyclopentanone in the CD-ring side chain, has a strong activity for enhancing bone growth, same as the reported compd., 2α-(3-hydroxypropoxy)-1α,25-dihydroxyvitamin D3 1d, and this deriv. shows a possibility that calcemic activity is less than 1d in vivo.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXlt1GhtrY%253D&md5=12dd7e9df84af32daa627455b5179b37

  105. 105

    Kashiwagi, H. ; Ono, Y. ; Ohta, M. ; Itoh, S. ; Ichikawa, F. ; Harada, S. ; Takeda, S. ; Sekiguchi, N. ; Ishigai, M. ; Takahashi, T. A series of nonsecosteroidal vitamin D receptor agonists for osteoporosis therapy. Bioorg. Med. Chem. 2013, 21 (7), 1823– 1833,  DOI: 10.1016/j.bmc.2013.01.042

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    105

    A series of nonsecosteroidal vitamin D receptor agonists for osteoporosis therapy

    Kashiwagi, Hirotaka; Ono, Yoshiyuki; Ohta, Masateru; Itoh, Susumu; Ichikawa, Fumihiko; Harada, Suguru; Takeda, Satoshi; Sekiguchi, Nobuo; Ishigai, Masaki; Takahashi, Tadakatsu

    Bioorganic & Medicinal Chemistry (2013), 21 (7), 1823-1833CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)

    In an extension of our study on gamma hydroxy carboxylic acid analogs, we explored a series of nonsecosteroidal vitamin D receptor (VDR) agonists in which 1,3-diol of 1,25(OH)2D3 had been replaced by aryl acetic acid. These analogs showed very potent activity in vitro compared with 1,25(OH)2D3. An X-ray anal. of trifluorophenyl acetic acid deriv. showed that the inserted Ph ring well mimicked the folded methylene linker of the gamma hydroxy carboxylic acid moiety but the carboxylic acid of trifluorophenyl acetic acid deriv. interacted with VDR in a different manner from gamma hydroxy carboxylic acids. Through our in vivo screening in an osteoporosis rat model using immature rats, we identified a potent active vitamin D3 analog, compd. CH5036249. In mature rats of the same model, compd. CH5036249 also showed good PK profiling and excellent ability to prevent bone mineral d. loss without severe hypercalcemia. Our nonsecosteroidal VDR agonist CH5036249 could be a possible new drug candidate for treating osteoporosis in human.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjtlyqtbo%253D&md5=5007f0d0fe822948826650d8f552bf96

  106. 106

    Saitoh, H. ; Watanabe, H. ; Kakuda, S. ; Takimoto-Kamimura, M. ; Takagi, K. ; Takeuchi, A. ; Takenouchi, K. Synthesis and biological activities of vitamin D3 derivatives with cyanoalkyl side chain at C-2 position. J. Steroid Biochem. Mol. Biol. 2015, 148 , 27– 30,  DOI: 10.1016/j.jsbmb.2014.12.004

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    106

    Synthesis and biological activities of vitamin D3 derivatives with cyanoalkyl side chain at C-2 position

    Saitoh, Hiroshi; Watanabe, Hidekazu; Kakuda, Shinji; Takimoto-Kamimura, Midori; Takagi, Kenichiro; Takeuchi, Akiko; Takenouchi, Kazuya

    Journal of Steroid Biochemistry and Molecular Biology (2015), 148 (), 27-30CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier Ltd.)

    The authors synthesized and evaluated novel vitamin D3 derivs. with cyanoalkyl side chain at C-2 position on the basis of their previous research for 2α side chain which bears nitrogen atom-contg. functional group. Through a study of X-ray co-crystal structures of human VDR (vitamin D receptor) and compd. 3, the authors demonstrated that the 2α alkyl side chain in compd. 3 shows a novel interaction in the complex of hVDR-LBD (ligand binding domain) and ligand. This article is part of a Special Issue entitled "17th Vitamin D Workshop".

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVyktLnL&md5=5af50c9c4a7c24d97afecaebfda68461

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    Sawada, D. ; Kakuda, S. ; Kamimura-Takimoto, M. ; Takeuchi, A. ; Matsumoto, Y. ; Kittaka, A. Revisiting the 7,8-cis-vitamin D3 derivatives: Synthesis, evaluating the biological activity, and study of the binding configuration. Tetrahedron 2016, 72 , 2838– 2848,  DOI: 10.1016/j.tet.2016.03.081

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    107

    Revisiting the 7,8-cis-vitamin D3 derivatives: synthesis, evaluating the biological activity, and study of the binding configuration

    Sawada, Daisuke; Kakuda, Shinji; Kamimura-Takimoto, Midori; Takeuchi, Akiko; Matsumoto, Yotaro; Kittaka, Atsushi

    Tetrahedron (2016), 72 (22), 2838-2848CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)

    Four 7,8-cis-1α,25-dihydroxyvitamin D3 derivs., 7,8-cis- and 7,8-cis-14-epi-1α,25-dihydroxy-19-norvitamin D3 as well as 7,8-cis- and 7,8-cis-14-epi-1α,25-dihydroxyvitamin D3 (I: R = HH, 14αH; R = HH, 14βH; R = CH2, 14αH; and R = CH2, 14βH, resp.) were synthesized, and their chem. stability was characterized. In our previous work, we disclosed that 14-epi-19-nortachysterol showed the unprecedented binding configuration in human vitamin D receptor (hVDR), i.e., 5,6- and 7,8-s-trans configuration. However, this configuration is variable because of the rotation at the single bond between C7 and C8. For the precise discussion of the 7,8-s-trans configuration, we designed and synthesized the 7,8-cis-locked skeleton of vitamin D3 derivs. Among four analogs, the 19-nor derivs. were stable at ambient temp., and their hVDR binding affinity and co-crystallog. anal. of their hVDR complexes were studied. The other derivs. with the triene system were isomerized to corresponding previtamin D3 and vitamin D3.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmsFyrurk%253D&md5=8cc64172bae3b48017d33e220adadc4b

  108. 108

    Ciesielski, F. ; Sato, Y. ; Chebaro, Y. ; Moras, D. ; Dejaegere, A. ; Rochel, N. Structural basis for the accommodation of bis- and tris-aromatic derivatives in vitamin D nuclear receptor. J. Med. Chem. 2012, 55 (19), 8440– 8449,  DOI: 10.1021/jm300858s

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    108

    Structural Basis for the Accommodation of Bis- and Tris-Aromatic Derivatives in Vitamin D Nuclear Receptor

    Ciesielski, Fabrice; Sato, Yoshiteru; Chebaro, Yassmine; Moras, Dino; Dejaegere, Annick; Rochel, Natacha

    Journal of Medicinal Chemistry (2012), 55 (19), 8440-8449CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    Actual use of the active form of vitamin D (calcitriol or 1α,25-dihydroxyvitamin D3) to treat hyperproliferative disorders is hampered by calcemic effects, hence the continuous development of chem. modified analogs with dissocd. profiles. Structurally distinct nonsecosteroidal analogs have been developed to mimic calcitriol activity profiles with low calcium serum levels. Here, we report the crystallog. study of vitamin D nuclear receptor (VDR) ligand binding domain in complexes with six nonsecosteroidal analogs harboring two or three Ph rings. These compds. induce a stimulated transcription in the nanomolar range, similar to calcitriol. Examn. of the protein-ligand interactions reveals the mode of binding of these nonsecosteroidal compds. and highlights the role of the various chem. modifications of the ligands to VDR binding and activity, notably (de)solvation effects. The structures with the tris-arom. ligands exhibit a rearrangement of a novel region of the VDR ligand binding pocket, helix H6.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlaisrrL&md5=724578a5c8622943869e60f02818076c

  109. 109

    Matsuo, M. ; Hasegawa, A. ; Takano, M. ; Saito, H. ; Kakuda, S. ; Chida, T. ; Takagi, K. ; Ochiai, E. ; Horie, K. ; Harada, Y. ; Takimoto-Kamimura, M. ; Takenouchi, K. ; Sawada, D. ; Kittaka, A. Synthesis of 2α-heteroarylalkyl active vitamin D3 with therapeutic effect on enhancing bone mineral density in vivo. ACS Med. Chem. Lett. 2013, 4 (7), 671– 674,  DOI: 10.1021/ml400098w

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    109

    Synthesis of 2α-Heteroarylalkyl Active Vitamin D3 with Therapeutic Effect on Enhancing Bone Mineral Density in Vivo

    Matsuo, Miki; Hasegawa, Asami; Takano, Masashi; Saito, Hiroshi; Kakuda, Shinji; Chida, Takayuki; Takagi, Ken-ichiro; Ochiai, Eiji; Horie, Kyohei; Harada, Yoshifumi; Takimoto-Kamimura, Midori; Takenouchi, Kazuya; Sawada, Daisuke; Kittaka, Atsushi

    ACS Medicinal Chemistry Letters (2013), 4 (7), 671-674CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)

    2α-Heteroarylethyl-1α,25-dihydroxyvitamin D3 analogs, which were designed to form a hydrogen bond between Arg274 of human vitamin D receptor (hVDR) and a nitrogen atom of the heteroarom. ring at the 2α-position, were synthesized. Among them, 2α-[2-(tetrazol-2-yl)ethyl]-1α,25-dihydroxyvitamin D3 (I) showed higher osteocalcin promoter transactivation activity in human osteosarcoma (HOS) cells and a greater therapeutic effect in ovariectomized (OVX) rats, osteoporosis model animals, on enhancing bone mineral d. than those of active vitamin D3. X-ray cocrystallog. anal. of the hVDR-ligand complex confirms that the new hydrogen bond formation stabilized the complex.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXosVehsr0%253D&md5=158cddc1b95b4e932c5d3c248e65904e

  110. 110

    Belorusova, A. Y. ; Eberhardt, J. ; Potier, N. ; Stote, R. H. ; Dejaegere, A. ; Rochel, N. Structural insights into the molecular mechanism of vitamin D receptor activation by lithocholic acid involving a new mode of ligand recognition. J. Med. Chem. 2014, 57 (11), 4710– 4719,  DOI: 10.1021/jm5002524

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    110

    Structural Insights into the Molecular Mechanism of Vitamin D Receptor Activation by Lithocholic Acid Involving a New Mode of Ligand Recognition

    Belorusova, Anna Y.; Eberhardt, Jerome; Potier, Noelle; Stote, Roland H.; Dejaegere, Annick; Rochel, Natacha

    Journal of Medicinal Chemistry (2014), 57 (11), 4710-4719CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    The vitamin D receptor (VDR), an endocrine nuclear receptor for 1α,25-dihydroxyvitamin D3, acts also as a bile acid sensor by binding lithocholic acid (LCA). The crystal structure of the zebrafish VDR ligand binding domain in complex with LCA and the SRC-2 coactivator peptide reveals the binding of two LCA mols. by VDR. One LCA binds to the canonical ligand-binding pocket, and the second one, which is not fully buried, is anchored to a site located on the VDR surface. Despite the low affinity of the alternative site, the binding of the second mol. promotes stabilization of the active receptor conformation. Biol. activity assays, structural anal., and mol. dynamics simulations indicate that the recognition of two ligand mols. is crucial for VDR agonism by LCA. The unique binding mode of LCA provides clues for the development of new chem. compds. that target alternative binding sites for therapeutic applications.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXnvVSgsL4%253D&md5=50a226bcf1efa2bd70c52a9d1014e873

  111. 111

    Zheng, J. ; Chang, M. R. ; Stites, R. E. ; Wang, Y. ; Bruning, J. B. ; Pascal, B. D. ; Novick, S. J. ; Garcia-Ordonez, R. D. ; Stayrook, K. R. ; Chalmers, M. J. ; Dodge, J. A. ; Griffin, P. R. HDX reveals the conformational dynamics of DNA sequence specific VDR co-activator interactions. Nat. Commun. 2017, 8 (1), 923,  DOI: 10.1038/s41467-017-00978-7

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    111

    HDX reveals the conformational dynamics of DNA sequence specific VDR co-activator interactions

    Zheng Jie; Chang Mi Ra; Pascal Bruce D; Novick Scott J; Garcia-Ordonez Ruben D; Griffin Patrick R; Stites Ryan E; Wang Yong; Stayrook Keith R; Chalmers Michael J; Dodge Jeffrey A; Bruning John B

    Nature communications (2017), 8 (1), 923 ISSN:.

    The vitamin D receptor/retinoid X receptor-α heterodimer (VDRRXRα) regulates bone mineralization via transcriptional control of osteocalcin (BGLAP) gene and is the receptor for 1α,25-dihydroxyvitamin D3 (1,25D3). However, supra-physiological levels of 1,25D3 activates the calcium-regulating gene TRPV6 leading to hypercalcemia. An approach to attenuate this adverse effect is to develop selective VDR modulators (VDRMs) that differentially activate BGLAP but not TRPV6. Here we present structural insight for the action of a VDRM compared with agonists by employing hydrogen/deuterium exchange. Agonist binding directs crosstalk between co-receptors upon DNA binding, stabilizing the activation function 2 (AF2) surfaces of both receptors driving steroid receptor co-activator-1 (SRC1) interaction. In contrast, AF2 of VDR within VDRM:BGLAP bound heterodimer is more vulnerable for large stabilization upon SRC1 interaction compared with VDRM:TRPV6 bound heterodimer. These results reveal that the combination of ligand structure and DNA sequence tailor the transcriptional activity of VDR toward specific target genes.The vitamin D receptor/retinoid X receptor-α heterodimer (VDRRXRα) regulates bone mineralization. Here the authors employ hydrogen/deuterium exchange (HDX) mass spectrometry to study the conformational dynamics of VDRRXRα and give mechanistic insights into how VDRRXRα controls the transcriptional activity of specific genes.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1M7gsFGjsg%253D%253D&md5=3017be55bc72c9489b3abbc814eb0657

  112. 112

    Sawada, D. ; Kakuda, S. ; Takeuchi, A. ; Kawagoe, F. ; Takimoto-Kamimura, M. ; Kittaka, A. Effects of 2-substitution on 14-epi-19-nortachysterol-mediated biological events: based on synthesis and X-ray co-crystallographic analysis with the human vitamin D receptor. Org. Biomol. Chem. 2018, 16 (14), 2448– 2455,  DOI: 10.1039/C8OB00158H

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    112

    Effects of 2-substitution on 14-epi-19-nortachysterol-mediated biological events: based on synthesis and X-ray co-crystallographic analysis with the human vitamin D receptor

    Sawada, Daisuke; Kakuda, Shinji; Takeuchi, Akiko; Kawagoe, Fumihiro; Takimoto-Kamimura, Midori; Kittaka, Atsushi

    Organic & Biomolecular Chemistry (2018), 16 (14), 2448-2455CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)

    Both 2α- and 2β-hydroxypropyl-substituted 14-epi-1α,25-dihydroxy-19-nortachysterols were synthesized to study the human vitamin D receptor (hVDR) binding affinity, binding configurations, and interactions with amino acid residues in the ligand binding domain of hVDR by x-ray co-crystallog. anal. In conjunction with our previous results on 14-epi-19-nortachysterol and 2-methylidene-, 2α-Me-, 2β-Me, and 2α-hydroxypropoxy-14-epi-19-nortachysterol, we propose a variety of effects of the substitution at the C2 position in the 14-epi-19-nortachysterol skeleton on the biol. activities.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXksFahur0%253D&md5=de6157a863f0f9c44efd1f13e6b92b6e

  113. 113

    Vanhooke, J. L. ; Benning, M. M. ; Bauer, C. B. ; Pike, J. W. ; DeLuca, H. F. Molecular structure of the rat vitamin D receptor ligand binding domain complexed with 2-carbon-substituted vitamin D3 hormone analogues and a LXXLL-containing coactivator peptide. Biochemistry 2004, 43 (14), 4101– 4110,  DOI: 10.1021/bi036056y

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    113

    Molecular structure of rat vitamin D receptor ligand binding domain complexed with 2-carbon-substituted vitamin D3 hormone analogs and a LXXLL-containing coactivator peptide

    Vanhooke, Janeen L.; Benning, Matthew M.; Bauer, Cary B.; Pike, J. Wesley; DeLuca, Hector F.

    Biochemistry (2004), 43 (14), 4101-4110CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)

    The authors have detd. the crystal structures of the ligand binding domain (LBD) of the rat vitamin D receptor in ternary complexes with a synthetic LXXLL-contg. peptide and the following four ligands: 1α,25-dihydroxyvitamin D3; 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3 (2MD); 1α-hydroxy-2-methylene-19-nor-(20S)-bishomopregnacalciferol (2MbisP), and 2α-methyl-19-nor-1α,25-dihydroxyvitamin D3 (2AM20R). The conformation of the LBD is identical in each complex. Binding of the 2-carbon-modified analogs does not change the positions of the amino acids in the ligand binding site and has no effect on the interactions in the coactivator binding pocket. The CD ring of the superpotent analog, 2MD, is tilted within the binding site relative to the other ligands in this study and to (20S)-1α,25-dihydroxyvitamin D3. The aliph. side chain of 2MD follows a different path within the binding site; nevertheless, the 25-hydroxyl group at the end of the chain occupies the same position as that of the natural ligand, and the hydrogen bonds with histidines 301 and 393 are maintained. 2MbisP binds to the receptor despite the absence of the 25-hydroxyl group. A water mol. is obsd. between His 301 and His 393 in this structure, and it preserves the orientation of the histidines in the binding site. Although the α-chair conformer is highly favored in soln. for the A ring of 2AM20R, the crystal structures demonstrate that this ring assumes the β-chair conformation in all cases, and the 1α-hydroxyl group is equatorial. The peptide folds as a helix and is anchored through hydrogen bonds to a surface groove formed by helixes 3, 4, and 12. Electrostatic and hydrophobic interactions between the peptide and the LBD stabilize the active receptor conformation. This stabilization appears necessary for crystal growth.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhvFWgs78%253D&md5=26aa0fd4025ce3cfe1f2952a4aa0dfa7

  114. 114

    Vanhooke, J. ; Tadi, B. ; Benning, M. ; Plum, L. ; DeLuca, H. New analogs of 2-methylene-19-nor-(20S)-1,25-dihydroxyvitamin D3 with conformationally restricted side chains: evaluation of biological activity and structural determination of VDR-bound conformations. Arch. Biochem. Biophys. 2007, 460 , 161– 165,  DOI: 10.1016/j.abb.2006.11.029

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    114

    New analogs of 2-methylene-19-nor-(20S)-1,25-dihydroxyvitamin D3 with conformationally restricted side chains: Evaluation of biological activity and structural determination of VDR-bound conformations

    Vanhooke, Janeen L.; Tadi, Bulli Padmaja; Benning, Matthew M.; Plum, Lori A.; DeLuca, Hector F.

    Archives of Biochemistry and Biophysics (2007), 460 (2), 161-165CODEN: ABBIA4; ISSN:0003-9861. (Elsevier)

    We have successfully prepd. E- and Z- isomers of 17-20 dehydro analogs of 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3 (2MD). Both isomers bind to the recombinant rat vitamin D receptor (VDR) with high affinity. The Z-isomer (Vit-III 17-20Z) displays activity in vivo and in vitro that is similar to 2MD. The in vitro activity of the E-isomer (Vit-III 17-20E) is comparable to the natural hormone, though in vivo this analog is significantly less calcemic. Crystal structures of the rat VDR ligand binding domain complexed with the analogs demonstrate that the Vit-III 17-20Z analog is oriented almost identically to 2MD, with only minor differences induced by the planar configuration around the C17-C20 double bond. The Vit-III 17-20E analog is oriented in a conformation distinct from both 2MD and the natural hormone. The structural comparisons suggest that the position of C21 in the ligand binding site may be an important determinant of biol. activity.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXksV2lt78%253D&md5=70d06048e2ada85d646ceb5359da60b8

  115. 115

    Kakuda, S. ; Okada, K. ; Eguchi, H. ; Takenouchi, K. ; Hakamata, W. ; Kurihara, M. ; Takimoto-Kamimura, M. Structure of the ligand-binding domain of rat VDR in complex with the nonsecosteroidal vitamin D3 analogue YR301. Acta Crystallogr., Sect. F: Struct. Biol. Cryst. Commun. 2008, 64 , 970– 973,  DOI: 10.1107/S1744309108026754

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    115

    Structure of the ligand-binding domain of rat VDR in complex with the nonsecosteroidal vitamin D3 analogue YR301

    Kakuda, Shinji; Okada, Kazuhisa; Eguchi, Hiroshi; Takenouchi, Kazuya; Hakamata, Wataru; Kurihara, Masaaki; Takimoto-Kamimura, Midori

    Acta Crystallographica, Section F: Structural Biology and Crystallization Communications (2008), 64 (11), 970-973CODEN: ACSFCL; ISSN:1744-3091. (International Union of Crystallography)

    Vitamin D receptor (VDR) is a ligand-inducible hormone receptor that mediates 1α,25(OH)2D3 action, regulating calcium and phosphate metab., induces potent cell differentiation activity and has immunosuppressive effects. Analogs of 1α,25(OH)2D3 have been used clin. for some years. However, the risk of potential side effects limits the use of these substances. LG190178 is a novel nonsecosteroidal ligand for VDR. (2S)-3-[4-(3-{4-[(2R)-2-hydroxy-3,3-dimethylbutoxy]-3-methylphenyl}pentan-3-yl)-2-methylphenoxy] propane-1,2-diol (YR301) is the only one of the four evaluated stereoisomers of LG190178 to have strong activity. To understand the strong activity of YR301, the crystal structure of YR301 complexed with the rat VDR ligand-binding domain (VDR LBD) was solved at 2.0 Å resoln. and compared with the structure of the VDR LBD-1α,25(OH)2D3 complex. YR301 and 1α,25(OH)2D3 share the same position and the diethylmethyl group occupies a similar space to the C and D rings of 1α,25(OH)2D3. YR301 has two characteristic hydroxyl groups which contribute to its potent activity. The first is 2'-OH, which forms hydrogen bonds to the NE2 atoms of both His301 and His393. The other is 2-OH, which interacts with Ser233 OG and Arg270 NH1. These two hydroxyl groups of YR301 correspond exactly to 25-OH and 1-OH, resp., of 1α,25(OH)2D3. The terminal hydroxyl group (3-OH) of YR301 is directly hydrogen bonded to Arg270 and also interacts indirectly with Tyr232 OH and the backbone NH of Asp144 via water mols. Addnl. derivatization of the terminal hydroxyl group using the positions of the water mols. might be useful for the design of more potent compds.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtlGgsLfL&md5=4ab4e98ace21ed3260a72d6771afb285

  116. 116

    Shimizu, M. ; Miyamoto, Y. ; Takaku, H. ; Matsuo, M. ; Nakabayashi, M. ; Masuno, H. ; Udagawa, N. ; DeLuca, H. ; Ikura, T. ; Ito, N. 2-Substituted-16-ene-22-thia-1α,25-dihydroxy-26,27-dimethyl-19-norvitamin D3 analogs: Synthesis, biological evaluation, and crystal structure. Bioorg. Med. Chem. 2008, 16 , 6949– 6964,  DOI: 10.1016/j.bmc.2008.05.043

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    116

    2-Substituted-16-ene-22-thia-1α,25-dihydroxy-26,27-dimethyl-19-norvitamin D3 analogs: Synthesis, biological evaluation, and crystal structure

    Shimizu, Masato; Miyamoto, Yukiko; Takaku, Hajime; Matsuo, Mayumi; Nakabayashi, Makoto; Masuno, Hiroyuki; Udagawa, Nobuyuki; DeLuca, Hector F.; Ikura, Teikichi; Ito, Nobutoshi

    Bioorganic & Medicinal Chemistry (2008), 16 (14), 6949-6964CODEN: BMECEP; ISSN:0968-0896. (Elsevier Ltd.)

    Recently, we have found that 16-ene-22-thia-26,27-dimethyl-19-norvitamin D3 analogs are 20 times more active than the natural hormone 1α,25-dihydroxyvitamin D3 in terms of transcriptional activity. To further investigate the effects of A-ring modification on the biol. activity profile, novel 22-thia-19-norvitamin D analogs bearing a hydroxyethoxy-, hydroxyethylidene- or Me group at C-2 in combination with 20S- and 20R-isomers were prepd. and tested for their in vitro biol. activities. All of the synthesized analogs showed 0.5-140% of the activity of the natural hormone in binding to the vitamin D receptor (VDR). When compared with the transcriptional activity of C-2 or C-20 isomeric pairs of the 22-thia analogs, the 20S-isomers were more potent than the 20R-isomers, and the 2β-hydroxyethoxy, 2E-hydroxyethylidene, and 2α-methyl-2β-hydroxy-22-thia isomers showed higher potency than their corresponding counterparts. In particular, I exhibited an extremely higher level of potency (210-fold) than the natural hormone. To elucidate the action mode of superagonist I at the mol. level, we detd. the crystal structures of the rat VDR-ligand-binding domain complexed with I or its 20R isomer in the presence of peptide contg. a nuclear box motif (LxxLL) at 1.9-2.0 Å resoln. The crystal structures demonstrated that the 1α-OH, 3β-OH, and 25-OH groups of the natural hormone and I were anchored by the same amino acid residues in the ligand-binding pocket, and the terminal OH moiety of the substituent at C-2 formed hydrogen bonds with Arg270 and a water mol. to create a tight water mol. network. Moreover, the Me groups at C-26a and C-27a make addnl. contact with hydrophobic residues such as Leu223, Ala227, Val230, and Ala299. These hydrophilic and hydrophobic interactions in I may underlie the induction of superagonistic activity.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXptVKqtro%253D&md5=a29590b46cbf7aec0ac1e9bd5853dac5

  117. 117

    Nakabayashi, M. ; Yamada, S. ; Yoshimoto, N. ; Tanaka, T. ; Igarashi, M. ; Ikura, T. ; Ito, N. ; Makishima, M. ; Tokiwa, H. ; DeLuca, H. ; Shimizu, M. Crystal structures of rat vitamin D receptor bound to adamantyl vitamin D analogs: structural basis for vitamin D receptor antagonism and partial agonism. J. Med. Chem. 2008, 51 , 5320– 5329,  DOI: 10.1021/jm8004477

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    117

    Crystal Structures of Rat Vitamin D Receptor Bound to Adamantyl Vitamin D Analogs: Structural Basis for Vitamin D Receptor Antagonism and Partial Agonism

    Nakabayashi, Makoto; Yamada, Sachiko; Yoshimoto, Nobuko; Tanaka, Takashi; Igarashi, Miharu; Ikura, Teikichi; Ito, Nobutoshi; Makishima, Makoto; Tokiwa, Hiroaki; DeLuca, Hector F.; Shimizu, Masato

    Journal of Medicinal Chemistry (2008), 51 (17), 5320-5329CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    The X-ray crystal structures of the rat VDR ligand-binding domain complexed with 19-norvitamin D compds. that contain an adamantyl substituent at the side-chain terminus, (ADTT), (ADNY), and (ADMI4) and a coactivator peptide derived from DRIP205 are reported. These compds. show a series of partial agonistic (10-75% efficacy)/antagonistic activities. All of these complexed receptors are crystd. in the canonical active conformation, regardless of their activity profiles. The bulky adamantyl side chain does not crowd helix 12 but protrudes into the gap formed by helix 11, loop 11-12, helix 3, and loop 6-7, thereby widening the ligand binding pocket. We suggest that these structural changes destabilize the active protein conformation and reduce its contribution to equil. among the active and inactive conformations. The coactivator peptide traps the minor active conformation, and the equil. shifts to the active conformation. As a result, these ligands show partial agonistic activities.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtVWmu7jJ&md5=860c8ed6f7ec43a44336abe85930e5fb

  118. 118

    Inaba, Y. ; Yoshimoto, N. ; Sakamaki, Y. ; Nakabayashi, M. ; Ikura, T. ; Tamamura, H. ; Ito, N. ; Shimizu, M. ; Yamamoto, K. A new class of vitamin D analogues that induce structural rearrangement of the ligand-binding pocket of the receptor. J. Med. Chem. 2009, 52 , 1438– 1449,  DOI: 10.1021/jm8014348

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    118

    A New Class of Vitamin D Analogues that Induce Structural Rearrangement of the Ligand-Binding Pocket of the Receptor

    Inaba, Yuka; Yoshimoto, Nobuko; Sakamaki, Yuta; Nakabayashi, Makoto; Ikura, Teikichi; Tamamura, Hirokazu; Ito, Nobutoshi; Shimizu, Masato; Yamamoto, Keiko

    Journal of Medicinal Chemistry (2009), 52 (5), 1438-1449CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    To identify novel vitamin D receptor (VDR) ligands that induce a novel architecture within the ligand-binding pocket (LBP), we have investigated eight 22-butyl-1α,24-dihydroxyvitamin D3 derivs. (3-10), all having a Bu group as the branched alkyl side chain. We found that the 22S-butyl-20-epi-25,26,27-trinorvitamin D deriv. 5 was a potent VDR agonist, whereas the corresponding compd. 4 with the natural configuration at C(20) was a potent VDR antagonist. Analogs with the full vitamin D3 side chain were less potent agonist, and whether they were agonists or antagonists depended on the 24-configuration. X-ray crystal structures demonstrated that the VDR-LBD accommodating the potent agonist 5 has an architecture wherein the lower side and the helix 11 side of the LBP is simply expanded relative to the canonical active-VDR situation; in contrast, the potent antagonist 4 induces an extra cavity to accommodate the branched moiety. This is the first report of a VDR antagonist that generates a new cavity to alter the canonical pocket structure of the ligand occupied VDR.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsFWgtLc%253D&md5=6e91b87520495a800b4656f99068fd79

  119. 119

    Inaba, Y. ; Nakabayashi, M. ; Itoh, T. ; Yoshimoto, N. ; Ikura, T. ; Ito, N. ; Shimizu, M. ; Yamamoto, K. 22S-butyl-1α,24R-dihydroxyvitamin D3: Recovery of vitamin D receptor agonistic activity. J. Steroid Biochem. Mol. Biol. 2010, 121 (1–2), 146– 150,  DOI: 10.1016/j.jsbmb.2010.02.033

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    119

    22S-Butyl-1α,24R-dihydroxyvitamin D3: Recovery of vitamin D receptor agonistic activity

    Inaba, Yuka; Nakabayashi, Makoto; Itoh, Toshimasa; Yoshimoto, Nobuko; Ikura, Teikichi; Ito, Nobutoshi; Shimizu, Masato; Yamamoto, Keiko

    Journal of Steroid Biochemistry and Molecular Biology (2010), 121 (1-2), 146-150CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier Ltd.)

    We recently reported that 22S-butyl-1α,24R-dihydroxyvitamin D3 (3) recovers the agonistic activity for vitamin D receptor (VDR), although its 25,26,27-trinor analog (2) is a potent VDR antagonist. To investigate the structural features involved in the recovery of agonism, we crystd. the ternary complex of VDR-ligand-binding domain, ligand 3 and coactivator peptide, and conducted X-ray crystallog. anal. of the complex. Compared with the complex with 2, the complex with 3 recovered the following structural features: a pincer-type hydrogen bond between the 24-hydroxyl group and VDR, the conformation of Leu305, the positioning of His301 and His393, the stability of the complex, and intimate hydrophobic interactions between the ligand and helix 12. In addn., we evaluated the potency of both compds. for recruiting RXR and coactivator. The results indicate that the complex with 3 generates a suitable surface for coactivator recruitment. These studies suggest that the action of 2 as an antagonist is caused by the generation of a surface not suitable for coactivator recruitment due to the lack of hydrophobic interactions with helix 12 as well as insufficient hydrogen bond formation between the 24-hydroxyl group and VDR. We concluded that the action of 3 as an agonist is based on the elimination of these structural defects in the complex with 2.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXptVCqtLs%253D&md5=e96d2ea299efb131687f2af51541bb17

  120. 120

    Demizu, Y. ; Takahashi, T. ; Kaneko, F. ; Sato, Y. ; Okuda, H. ; Ochiai, E. ; Horie, K. ; Takagi, K. ; Kakuda, S. ; Takimoto-Kamimura, M. ; Kurihara, M. Design, synthesis and X-ray crystallographic study of new nonsecosteroidal vitamin D receptor ligands. Bioorg. Med. Chem. Lett. 2011, 21 (20), 6104– 6107,  DOI: 10.1016/j.bmcl.2011.08.047

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    120

    Design, synthesis and X-ray crystallographic study of new nonsecosteroidal vitamin D receptor ligands

    Demizu, Yosuke; Takahashi, Takeo; Kaneko, Fumiya; Sato, Yukiko; Okuda, Haruhiro; Ochiai, Eiji; Horie, Kyohei; Takagi, Ken-ichiro; Kakuda, Shinji; Takimoto-Kamimura, Midori; Kurihara, Masaaki

    Bioorganic & Medicinal Chemistry Letters (2011), 21 (20), 6104-6107CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)

    Nonsecosteroidal vitamin D receptor (VDR) ligands that formed H-bonds with six amino acid residues (Tyr143, Ser233, Arg270, Ser274, His301 and His393) of the VDR ligand-binding domain were designed and synthesized. The ligand YR335 (I) exhibited potent transcriptional activity, which was comparable to those of 1α,25-dihydroxyvitamin D3 and YR301. The crystal structure of the complex formed between YR335 and the VDR ligand-binding domain was solved, which revealed that YR335 formed H-bonds with the six amino acid residues mentioned above.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtF2ru7fL&md5=d63570dcce46f8e9718b63820e7c10ae

  121. 121

    Nakabayashi, M. ; Tsukahara, Y. ; Iwasaki-Miyamoto, Y. ; Mihori-Shimazaki, M. ; Yamada, S. ; Inaba, S. ; Oda, M. ; Shimizu, M. ; Makishima, M. ; Tokiwa, H. ; Ikura, T. ; Ito, N. Crystal structures of hereditary vitamin D-resistant rickets-associated vitamin D receptor mutants R270L and W282R bound to 1,25-dihydroxyvitamin D3 and synthetic ligands. J. Med. Chem. 2013, 56 (17), 6745– 6760,  DOI: 10.1021/jm400537h

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    121

    Crystal structures of hereditary vitamin D-resistant rickets-associated vitamin D receptor mutants R270L and W282R bound to 1,25-dihydroxyvitamin D3 and synthetic ligands

    Nakabayashi, Makoto; Tsukahara, Yoshito; Iwasaki-Miyamoto, Yukiko; Mihori-Shimazaki, Mika; Yamada, Sachiko; Inaba, Satomi; Oda, Masayuki; Shimizu, Masato; Makishima, Makoto; Tokiwa, Hiroaki; Ikura, Teikichi; Ito, Nobutoshi

    Journal of Medicinal Chemistry (2013), 56 (17), 6745-6760CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    The vitamin D receptor (VDR), a member of the nuclear receptor superfamily, functions as a ligand-dependent transcription factor for various genes. Hereditary vitamin D-resistant rickets (HVDRR), an autosomal recessive disease, is caused by mutations in the VDR. In particular, the missense mutations R274L and W286R in the ligand-binding domain of the VDR can severely reduce or even eliminate natural hormone responsiveness. Here, we report a crystal structure anal. of the R270L and W282R mutants of rat VDR (human R274L and W286R, resp.) in complex with the natural hormone and synthetic ligands. We also studied the folding properties of the mutant proteins by using CD spectra. Our study indicates that these mutations result in only local structural modifications. We discuss why these mutations disrupt the VDR function and provide clues to develop effective ligands for the treatment of HVDRR.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1Oju77N&md5=544e9b725fe2349ccc46108d01d2d39d

  122. 122

    Kudo, T. ; Ishizawa, M. ; Maekawa, K. ; Nakabayashi, M. ; Watarai, Y. ; Uchida, H. ; Tokiwa, H. ; Ikura, T. ; Ito, N. ; Makishima, M. ; Yamada, S. Combination of triple bond and adamantane ring on the vitamin D side chain produced partial agonists for vitamin D receptor. J. Med. Chem. 2014, 57 (10), 4073– 4087,  DOI: 10.1021/jm401989c

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    122

    Combination of Triple Bond and Adamantane Ring on the Vitamin D Side Chain Produced Partial Agonists for Vitamin D Receptor

    Kudo, Takeru; Ishizawa, Michiyasu; Maekawa, Kazuki; Nakabayashi, Makoto; Watarai, Yusuke; Uchida, Hikaru; Tokiwa, Hiroaki; Ikura, Teikichi; Ito, Nobutoshi; Makishima, Makoto; Yamada, Sachiko

    Journal of Medicinal Chemistry (2014), 57 (10), 4073-4087CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    Vitamin D receptor (VDR) ligands are therapeutic agents that are used for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism and have immense potential as therapeutic agents for autoimmune diseases, cancers, and cardiovascular diseases. However, the major side effect of VDR ligands, the development of hypercalcemia, limits their expanded use. To develop tissue-selective VDR modulators, we have designed vitamin D analogs with an adamantane ring at the side chain terminal, which would interfere with helix 12, the activation function 2, and modulate the VDR potency. Here we report 25- or 26-adamantyl-23,23,24,24-tetradehydro-19-norvitamin D derivs. I (n = 0, 25R and 25S; n = 1, 25R and 25S). These compds. showed high VDR affinities (90% at max.), partial agonistic activities (EC50 10-9-10-8 M with 40-80% efficacy) in transactivation, and tissue-selective activity in target gene expressions. We investigate the structure-activity relationships of these compds. on the basis of their X-ray crystal structures.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXntFChtL4%253D&md5=f32bfe6bcc8087925abd70a34a2a9677

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    Asano, L. ; Ito, I. ; Kuwabara, N. ; Waku, T. ; Yanagisawa, J. ; Miyachi, H. ; Shimizu, T. Structural basis for vitamin D receptor agonism by novel non-secosteroidal ligands. FEBS Lett. 2013, 587 , 957– 963,  DOI: 10.1016/j.febslet.2013.02.028

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    123

    Structural basis for vitamin D receptor agonism by novel non-secosteroidal ligands

    Asano, Lisa; Ito, Ichiaki; Kuwabara, Naoyuki; Waku, Tsuyoshi; Yanagisawa, Junn; Miyachi, Hiroyuki; Shimizu, Toshiyuki

    FEBS Letters (2013), 587 (7), 957-963CODEN: FEBLAL; ISSN:0014-5793. (Elsevier B.V.)

    Non-secosteroidal ligands for vitamin D receptor (VDR) have been developed for the agonist with non-calcemic profiles. Here, we provide the structural mechanism of VDR agonism by novel non-secosteroidal ligands. All ligands had the similar efficacy, while two had the higher potency. Crystallog. analyses revealed that all ligands interacted with helix H10 and the loop between helixes H6 and H7 in a similar manner, but also that the two ligands with higher potency had different interaction modes. This study suggests that distinct ligand potency depend upon differences in the formation and rearrangement of hydrogen-bond networks induced by each ligand.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjvVOnsrg%253D&md5=a2f9b100e5e6843728a7d9fc3a7c7b07

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    Masuno, H. ; Ikura, T. ; Morizono, D. ; Orita, I. ; Yamada, S. ; Shimizu, M. ; Ito, N. Crystal structures of complexes of vitamin D receptor ligand-binding domain with lithocholic acid derivatives. J. Lipid Res. 2013, 54 (8), 2206– 2213,  DOI: 10.1194/jlr.M038307

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    124

    Crystal structures of complexes of vitamin D receptor ligand-binding domain with lithocholic acid derivatives

    Masuno, Hiroyuki; Ikura, Teikichi; Morizono, Daisuke; Orita, Isamu; Yamada, Sachiko; Shimizu, Masato; Ito, Nobutoshi

    Journal of Lipid Research (2013), 54 (8), 2206-2213CODEN: JLPRAW; ISSN:0022-2275. (American Society for Biochemistry and Molecular Biology, Inc.)

    The secondary bile acid lithocholic acid LCA and its derivs. act as selective modulators of the vitamin D receptor VDR, although their structures fundamentally differ from that of the natural hormone 1α,25-dihydroxyvitamin D3 1,25 OH 2D3. Here, we have detd. the crystal structures of the ligand-binding domain of rat VDR VDR-LBD in ternary complexes with a synthetic partial peptide of the coactivator MED1 mediator of RNA polymerase II transcription subunit (1) and four ligands, LCA, 3-keto LCA, LCA acetate, and LCA propionate, with the goal of elucidating their agonistic mechanism. LCA and its derivs. bind to the same ligand-binding pocket LBP of VDR-LBD that 1,25 OH 2D3 binds to, but in the opposite orientation; their A-ring is positioned at the top of the LBP, whereas their acyclic tail is located at the bottom of the LBP. However, most of the hydrophobic and hydrophilic interactions obsd. in the complex with 1,25 OH 2D3 are reproduced in the complexes with LCA and its derivs. Addnl. interactions between VDR-LBD and the C-3 substituents of the A-ring are also obsd. in the complexes with LCA and its derivs. These may result in the obsd. difference in the potency among the LCA-type ligands.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVOrsb7I&md5=8ec407eb03459db64116211db574e02b

  125. 125

    Anami, Y. ; Itoh, T. ; Egawa, D. ; Yoshimoto, N. ; Yamamoto, K. A mixed population of antagonist and agonist binding conformers in a single crystal explains partial agonism against vitamin D receptor: active vitamin D analogues with 22R-alkyl group. J. Med. Chem. 2014, 57 (10), 4351– 4367,  DOI: 10.1021/jm500392t

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    125

    A Mixed Population of Antagonist and Agonist Binding Conformers in a Single Crystal Explains Partial Agonism against Vitamin D Receptor: Active Vitamin D Analogues with 22R-Alkyl Group

    Anami, Yasuaki; Itoh, Toshimasa; Egawa, Daichi; Yoshimoto, Nobuko; Yamamoto, Keiko

    Journal of Medicinal Chemistry (2014), 57 (10), 4351-4367CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    We are continuing to study the structural basis of vitamin D receptor (VDR) agonism and antagonism by using 22S-alkyl vitamin D analogs. Here we report the synthesis and biol. evaluation of 22R-alkyl analogs and the X-ray crystallog. anal. of vitamin D receptor ligand-binding domain (VDR-LBD) complexed with a 22R-analog. VDR-LBD complexed with the partial agonist 8a showed that 8a binds to VDR-LBD with two conformations, one of which is the antagonist/VDR-LBD complex structure and the other is the agonist/VDR-LBD complex structure. The results indicate that the partial agonist activity of 8a depends on the sum of antagonistic and agonistic activities caused by the antagonist and agonist binding conformers, resp. The structural basis obsd. here must be applicable to the partial agonism of other ligand-dependent nuclear receptors. This is the first report describing the trapping of a conformational subset of the ligand and the nuclear receptor in a single crystal.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXmsFWgu70%253D&md5=e641715c565e9cb099b46665eb486661

  126. 126

    Watarai, Y. ; Ishizawa, M. ; Ikura, T. ; Zacconi, F. C. ; Uno, S. ; Ito, N. ; Mouriño, A. ; Tokiwa, H. ; Makishima, M. ; Yamada, S. Synthesis, biological activities, and X-ray crystal structural analysis of 25-hydroxy-25(or 26)-adamantyl-17-[20(22),23-diynyl]-21-norvitamin D compounds. J. Med. Chem. 2015, 58 (24), 9510– 9521,  DOI: 10.1021/acs.jmedchem.5b00792

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    126

    Synthesis, Biological Activities, and X-ray Crystal Structural Analysis of 25-Hydroxy-25(or 26)-adamantyl-17-[20(22),23-diynyl]-21-norvitamin D Compounds

    Watarai, Yusuke; Ishizawa, Michiyasu; Ikura, Teikichi; Zacconi, Flavia C. M.; Uno, Shigeyuki; Ito, Nobutoshi; Mourino, Antonio; Tokiwa, Hiroaki; Makishima, Makoto; Yamada, Sachiko

    Journal of Medicinal Chemistry (2015), 58 (24), 9510-9521CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    Novel 19-norvitamin D analogs (ADYW1-4) in which an adamantyl diyne side chain is attached directly to the 17-position of the D ring are designed and stereoselectively synthesized. The adamantane ring of these analogs was expected to interfere with helix 12 (H12, activation function 2) of the vitamin D receptor (VDR) to modulate its activities. The analog I binds to the VDR (7% of the natural hormone) and shows significant partial agonistic activity in transactivation assay. Compd. I showed considerable selectivity in VDR target genes expressions in vitro, it was taken up by target cells 2-3 times more readily, and its lifetime was three times longer than the natural hormone. The X-ray crystal structure of I in complex with VDR reveals that the ligand binds similarly to the natural hormone, but the diyne moiety is slightly bent (angles around the diyne 5° to 8°) with respect to the original diyne vitamin D compd. II in VDR (<1°) due to steric hindrance with helix 12.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvFWmu73P&md5=49c3044eb753c13e9af4429d4991465e

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    Anami, Y. ; Sakamaki, Y. ; Itoh, T. ; Inaba, Y. ; Nakabayashi, M. ; Ikura, T. ; Ito, N. ; Yamamoto, K. Fine tuning of agonistic/antagonistic activity for vitamin D receptor by 22-alkyl chain length of ligands: 22S-Hexyl compound unexpectedly restored agonistic activity. Bioorg. Med. Chem. 2015, 23 (22), 7274– 7281,  DOI: 10.1016/j.bmc.2015.10.026

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    127

    Fine tuning of agonistic/antagonistic activity for vitamin D receptor by 22-alkyl chain length of ligands: 22S-Hexyl compound unexpectedly restored agonistic activity

    Anami, Yasuaki; Sakamaki, Yuta; Itoh, Toshimasa; Inaba, Yuka; Nakabayashi, Makoto; Ikura, Teikichi; Ito, Nobutoshi; Yamamoto, Keiko

    Bioorganic & Medicinal Chemistry (2015), 23 (22), 7274-7281CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)

    1α,25-Dihydroxyvitamin D3 exerts its actions by binding to vitamin D receptor (VDR). The authors are continuing the study related to the alteration of pocket structure of VDR by 22-alkyl substituent of ligands and the relationships between the alteration and agonistic/antagonistic activity. Previously the authors reported that compds. 2 (22-H), 3 (22S-Et), and 4 (22S-Bu) are VDR agonist, partial agonist and antagonist, resp. Here, the authors describe the synthesis and biol. evaluation of 22S-hexyl analog 5 (22S-Hexyl-2-methyfidene-19,25,26,27-tetranor-1α,25-dihydroxyvitamin D3 (22S-Hex)), which was designed to be a stronger VDR antagonist than 4. Unexpectedly, 5 showed partial agonistic but not antagonistic activity when bound to VDR, indicating that it is not necessarily true that the bulkier the side chain is, the stronger the antagonistic activity will be. X-ray crystallog. anal. of the VDR-ligand-binding domain (VDR-LBD) accommodating compd. 5 indicated that the partial agonist activity of 5 is dependent on the mixed population of the agonistic and antagonistic conformations. Binding of compd. 5 may not bring the complex into the only antagonistic conformation due to the large conformational change of the VDR-LBD. From this study fine tuning of agonistic/antagonistic activity for VDR is possible by 22-alkyl chain length of ligands.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslSjsLvJ&md5=b3354de77c5be84f0cf49c4401092dcb

  128. 128

    Anami, Y. ; Shimizu, N. ; Ekimoto, T. ; Egawa, D. ; Itoh, T. ; Ikeguchi, M. ; Yamamoto, K. Apo- and antagonist-binding structures of vitamin D receptor ligand-binding domain revealed by hybrid approach combining small-angle X-ray scattering and molecular dynamics. J. Med. Chem. 2016, 59 (17), 7888– 7900,  DOI: 10.1021/acs.jmedchem.6b00682

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    128

    Apo- and Antagonist-Binding Structures of Vitamin D Receptor Ligand-Binding Domain Revealed by Hybrid Approach Combining Small-Angle X-ray Scattering and Molecular Dynamics

    Anami, Yasuaki; Shimizu, Nobutaka; Ekimoto, Toru; Egawa, Daichi; Itoh, Toshimasa; Ikeguchi, Mitsunori; Yamamoto, Keiko

    Journal of Medicinal Chemistry (2016), 59 (17), 7888-7900CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    Vitamin D receptor (VDR) controls the expression of numerous genes through the conformational change caused by binding 1α,25-dihydroxyvitamin D3. Helix 12 in the ligand-binding domain (LBD) is key to regulating VDR activation. The structures of apo VDR-LBD and the VDR-LBD/antagonist complex are unclear. Here, we reveal their unprecedented structures in soln. using a hybrid method combining small-angle X-ray scattering and mol. dynamics simulations. In apo rat VDR-LBD, helix 12 is partially unraveled, and it is positioned around the canonical active position and fluctuates. Helix 11 greatly bends toward the outside at Q396, creating a kink. In the rat VDR-LBD/antagonist complex, helix 12 does not generate the activation function 2 surface, and loop 11-12 is remarkably flexible compared to that in the apo rat VDR-LBD. On the basis of these structural insights, we propose a "folding-door model" to describe the mechanism of agonism/antagonism of VDR-LBD.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlOgt7%252FF&md5=8b36a50cec586e1171911c07106b84c5

  129. 129

    Kato, A. ; Itoh, T. ; Anami, Y. ; Egawa, D. ; Yamamoto, K. Helix12-stabilization antagonist of vitamin D receptor. Bioconjugate Chem. 2016, 27 (7), 1750– 1761,  DOI: 10.1021/acs.bioconjchem.6b00246

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    129

    Helix12-Stabilization Antagonist of Vitamin D Receptor

    Kato, Akira; Itoh, Toshimasa; Anami, Yasuaki; Egawa, Daichi; Yamamoto, Keiko

    Bioconjugate Chemistry (2016), 27 (7), 1750-1761CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)

    To develop strong vitamin D receptor (VDR) antagonists and reveal their antagonistic mechanism, we designed and synthesized vitamin D analogs with bulky side chains based on the "active antagonist" concept in which antagonist prevents helix 12 (H12) folding. Of the synthesized analogs, compds. 3a and 3b showed strong antagonistic activity. Dynamic hydrogen/deuterium exchange coupled with mass spectrometry (HDX-MS) and static X-ray crystal structure analyses indicated that compd. 3a stabilizes H11-H12 but displaces H6-H7 so that 3a is a novel rather than "active" or "passive" type of antagonist. We classified 3a as a third type of antagonist and called it "H11-H12 stabilization antagonist". HDX-MS anal. indicated that antagonist 3b is an "active" antagonist. To date there are no reports relating to nuclear receptor antagonist that strongly stabilizes H12. In this study, we found first VDR antagonist that stabilizes H12 and we showed that antagonistic mechanism is diverse depending on each antagonist structure. Addnl., HDX-MS was proven to be very useful for investigations of protein structure alterations resulting from ligand binding.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XpsF2mu7k%253D&md5=611720db42fee11163c65534536f9522

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    Asano, L. ; Waku, T. ; Abe, R. ; Kuwabara, N. ; Ito, I. ; Yanagisawa, J. ; Nagasawa, K. ; Shimizu, T. Regulation of the vitamin D receptor by vitamin D lactam derivatives. FEBS Lett. 2016, 590 (18), 3270– 3279,  DOI: 10.1002/1873-3468.12348

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    130

    Regulation of the vitamin D receptor by vitamin D lactam derivatives

    Asano, Lisa; Waku, Tsuyoshi; Abe, Rumi; Kuwabara, Naoyuki; Ito, Ichiaki; Yanagisawa, Junn; Nagasawa, Kazuo; Shimizu, Toshiyuki

    FEBS Letters (2016), 590 (18), 3270-3279CODEN: FEBLAL; ISSN:0014-5793. (Wiley-Blackwell)

    The active metabolite of vitamin D3, 1α,25-dihydroxyvitamin D3, acts as a ligand for the vitamin D receptor (VDR) and activates VDR-mediated gene expression. Recently, we characterized 1α,25-dihydroxyvitamin D3-26,23-lactams (DLAMs), which mimic vitamin D3 metabolites, as non-calcemic VDR ligands that barely activate the receptor. In this study, we present structural insights onto the regulation of VDR function by DLAMs. X-ray crystallog. anal. revealed that DLAMs induced a large conformational change in the loop region between helixes H6 and H7 in the VDR ligand-binding domain. Our structural anal. suggests that targeting of the loop region may be a new mode of VDR regulation. This article is protected by copyright. All rights reserved.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht12ksLnI&md5=50f2b628e1ece0ec123a9b483726152a

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    Egawa, D. ; Itoh, T. ; Kato, A. ; Kataoka, S. ; Anami, Y. ; Yamamoto, K. SRC2–3 binds to vitamin D receptor with high sensitivity and strong affinity. Bioorg. Med. Chem. 2017, 25 (2), 568– 574,  DOI: 10.1016/j.bmc.2016.11.020

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    131

    SRC2-3 binds to vitamin D receptor with high sensitivity and strong affinity

    Egawa, Daichi; Itoh, Toshimasa; Kato, Akira; Kataoka, Saori; Anami, Yasuaki; Yamamoto, Keiko

    Bioorganic & Medicinal Chemistry (2017), 25 (2), 568-574CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)

    Vitamin D receptor (VDR) is a member of the nuclear receptor superfamily and regulates the expression of target genes through ligand binding. To express the target gene, coactivator binding to the VDR/ligand complex is essential. Although there are many coactivators in living cells, precise interactions between coactivators and VDR have not been clarified. Here, we synthesized two coactivator peptides, DRIP205-2 and SRC2-3, evaluated their affinity for the ligand-binding domain (LBD) of VDR using 1α,25-dihydroxyvitamin D3, partial agonist 1, and antagonist 2 by surface plasmon resonance (SPR), and assessed their interaction modes with VDR-LBD using X-ray crystallog. anal. This study showed that the SRC2-3 peptide is more sensitive to the ligands (agonist, partial agonist, and antagonist) and shows more intimate interactions with VDR-LBD than DRIP205-2 peptide.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvFCnsr7F&md5=dfec0223b6da7a00943fda6fb7980b74

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    Kato, A. ; Yamao, M. ; Hashihara, Y. ; Ishida, H. ; Itoh, T. ; Yamamoto, K. Vitamin D analogues with a p-hydroxyphenyl group at the C25 position: Crystal structure of vitamin D receptor ligand-binding domain complexed with the ligand explains the mechanism underlying full antagonistic action. J. Med. Chem. 2017, 60 (20), 8394– 8406,  DOI: 10.1021/acs.jmedchem.7b00819

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    132

    Vitamin D Analogues with a p-Hydroxyphenyl Group at the C25 Position: Crystal Structure of Vitamin D Receptor Ligand-Binding Domain Complexed with the Ligand Explains the Mechanism Underlying Full Antagonistic Action

    Kato, Akira; Yamao, Makiko; Hashihara, Yuta; Ishida, Hiroaki; Itoh, Toshimasa; Yamamoto, Keiko

    Journal of Medicinal Chemistry (2017), 60 (20), 8394-8406CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    Vitamin D receptor (VDR) antagonists can be classified into two categories: the first category of VDR antagonists, which do not stabilize the helix 11-12, and the second category of antagonists, which destabilize the helix 6-7 region. To elucidate the mechanism underlying the first category antagonists by using the crystal structure, the authors designed and synthesized several VDR ligands with a p-hydroxyphenyl group at the C25-position. Of these, 22S-butyl-25-carbonyl analog 5b and 25-di-p-hydroxyphenyl analogs 6a,b showed strong antagonistic activity. The authors succeeded in cocrystg. the ligand-binding domain of VDR complexed with 5b (22S-butyl-25-(4'-hydroxyphenyl)-2-methylidene-19,26,27-trinor-25-oxo-1α-hydroxyitamin D3) and found that the structure showed an alternative conformation of the helix 11-12 that explained the mechanism of the first category antagonists. Taking the present and previous studies together, the authors could elucidate the mechanisms underlying first and second categories antagonists based on individual crystal structures. This study provides significant insights into antagonism against not only VDR but also nuclear receptors.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFOjtb7N&md5=4172e9257d7a3465901ee7bc9e5bbfe2

  133. 133

    Otero, R. ; Ishizawa, M. ; Numoto, N. ; Ikura, T. ; Ito, N. ; Tokiwa, H. ; Mouriño, A. ; Makishima, M. ; Yamada, S. 25 S-Adamantyl-23-yne-26,27-dinor-1α,25-dihydroxyvitamin D3: synthesis, tissue selective bological activities, and X-ray crystal structural analysis of its vitamin D receptor complex. J. Med. Chem. 2018, 61 (15), 6658– 6673,  DOI: 10.1021/acs.jmedchem.8b00427

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    133

    25S-Adamantyl-23-yne-26,27-dinor-1α,25-dihydroxyvitamin D3: Synthesis, Tissue Selective Biological Activities, and X-ray Crystal Structural Analysis of Its Vitamin D Receptor Complex

    Otero, Rocio; Ishizawa, Michiyasu; Numoto, Nobutaka; Ikura, Teikichi; Ito, Nobutoshi; Tokiwa, Hiroaki; Mourino, Antonio; Makishima, Makoto; Yamada, Sachiko

    Journal of Medicinal Chemistry (2018), 61 (15), 6658-6673CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    Both 25R- and 25S-25-adamantyl-23-yne-26,27-dinor-1α,25-dihydroxyvitamin D3 were stereoselectively synthesized by a Pd(0)-catalyzed ring closure and Suzuki-Miyaura coupling between enol-triflate and alkenyl-boronic ester. The 25S isomer showed high vitamin D receptor (VDR) affinity (50% of that of the natural hormone 1α,25-dihydroxyvitamin D3, (I)) and transactivation potency (kidney HEK293, 90%). In endogenous gene expression, it showed high cell-type selectivity for kidney cells (HEK293, CYP24A1 160% of I), bone cells (MG63, osteocalcin 64%), and monocytes (U937, CAMP 96%) over intestine (SW480, CYP24A1 8%) and skin (HaCaT, CYP24A1 7%) cells. The X-ray crystal structural anal. of the 25S isomer in complex with rat VDR-ligand binding domain (LBD) showed the highest Cα positional shift from the I/VDR-LBD complex at helix 11. Helix 11 of the 25S isomer and I VDR-LBD complexes also showed significant differences in surface properties. These results suggest that the 25S isomer should be examd. further as another candidate for a mild preventive osteoporosis agent.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXht12jsbvL&md5=e0e29359d895ca4fffcdb60493b5c286

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    Yoshizawa, M. ; Itoh, T. ; Hori, T. ; Kato, A. ; Anami, Y. ; Yoshimoto, N. ; Yamamoto, K. Identification of the histidine residue in vitamin D receptor that covalently binds to electrophilic ligands. J. Med. Chem. 2018, 61 (14), 6339– 6349,  DOI: 10.1021/acs.jmedchem.8b00774

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    134

    Identification of the Histidine Residue in Vitamin D Receptor That Covalently Binds to Electrophilic Ligands

    Yoshizawa, Mami; Itoh, Toshimasa; Hori, Tatsuya; Kato, Akira; Anami, Yasuaki; Yoshimoto, Nobuko; Yamamoto, Keiko

    Journal of Medicinal Chemistry (2018), 61 (14), 6339-6349CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    We designed and synthesized vitamin D analogs with an electrophile as covalent modifiers for the vitamin D receptor (VDR). Novel vitamin D analogs 1-4 have an electrophilic enone group at the side chain for conjugate addn. to His301 or His393 in the VDR. All compds. showed specific VDR-binding potency and agonistic activity. Covalent bond formations of 1-4 with the ligand-binding domain (LBD) of VDR were evaluated by electrospray ionization mass spectrometry. All compds. were shown to covalently bind to the VDR-LBD, and the abundance of VDR-LBD corresponding conjugate adducts of 1-4 increased with incubation time. Enone compds. 1 and 2 showed higher reactivity than the ene-ynone 3 and dienone 4 compds. Furthermore, we successfully obtained cocrystals of VDR-LBD with analogs 1-4. X-ray crystallog. anal. showed a covalent bond with His301 in VDR-LBD. We successfully synthesized vitamin D analogs that form a covalent bond with VDR-LBD.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtF2htLzN&md5=5cc7c5b614f89aaa7582a0a25225e2e8

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    Rochel, N. ; Hourai, S. ; Perez-Garcia, X. ; Rumbo, A. ; Mouriño, A. ; Moras, D. Crystal structure of the vitamin D nuclear receptor ligand binding domain in complex with a locked side chain analog of calcitriol. Arch. Biochem. Biophys. 2007, 460 (2), 172– 176,  DOI: 10.1016/j.abb.2007.01.031

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    135

    Crystal structure of the vitamin D nuclear receptor ligand binding domain in complex with a locked side chain analog of calcitriol

    Rochel, Natacha; Hourai, Shinji; Perez-Garcia, Xenxo; Rumbo, Antonio; Mourino, Antonio; Moras, Dino

    Archives of Biochemistry and Biophysics (2007), 460 (2), 172-176CODEN: ABBIA4; ISSN:0003-9861. (Elsevier)

    The crystal structures of vitamin D nuclear receptor (VDR) have revealed that all compds. are anchored by the same residues to the ligand binding pocket (LBP). Based on this observation, a synthetic analog with a locked side chain (21-nor-calcitriol-20(22),23-diyne) has been synthesized in order to gain in entropy energy with a predefined active side chain conformation. The crystal structure of VDR LBD bound to this locked side chain analog while confirming the docking provides a structural basis for the activity of this compd.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXksV2lt70%253D&md5=023a1cc9dd681a7565e3247aa423fc47

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    Ciesielski, F. ; Rochel, N. ; Moras, D. Adaptability of the vitamin D nuclear receptor to the synthetic ligand Gemini: remodelling the LBP with one side chain rotation. J. Steroid Biochem. Mol. Biol. 2007, 103 , 235– 242,  DOI: 10.1016/j.jsbmb.2006.12.003

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    136

    Adaptability of the Vitamin D nuclear receptor to the synthetic ligand Gemini: Remodelling the LBP with one side chain rotation

    Ciesielski, Fabrice; Rochel, Natacha; Moras, Dino

    Journal of Steroid Biochemistry and Molecular Biology (2007), 103 (3-5), 235-242CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier Ltd.)

    The crystal structure of the ligand binding domain (LBD) of the wild-type Vitamin D receptor (VDR) of zebrafish bound to Gemini, a synthetic agonist ligand with two identical side chains branching at carbon 20 reveals a ligand-dependent structural rearrangement of the ligand binding pocket (LBP). The rotation of a Leu side chain opens the access to a channel that can accommodate the second side chain of the ligand. The 25% increase of the LBP's vol. does not alter the essential agonist features of VDR. The possibility to adapt the LBP to novel ligands with different chem. and/or structure opens new perspectives in the design of more specifically targeted ligands.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjt1WgtLs%253D&md5=56d0b3390dbbf73182efb910aaecd8d8

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    Eelen, G. ; Valle, N. ; Sato, Y. ; Rochel, N. ; Verlinden, L. ; De Clercq, P. ; Moras, D. ; Bouillon, R. ; Muñoz, A. ; Verstuyf, A. Superagonistic fluorinated vitamin D3 analogs stabilize helix 12 of the vitamin D receptor. Chem. Biol. 2008, 15 (10), 1029– 1034,  DOI: 10.1016/j.chembiol.2008.08.008

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    137

    Superagonistic Fluorinated Vitamin D3 Analogs Stabilize Helix 12 of the Vitamin D Receptor

    Eelen, Guy; Valle, Noelia; Sato, Yoshiteru; Rochel, Natacha; Verlinden, Lieve; De Clercq, Pierre; Moras, Dino; Bouillon, Roger; Munoz, Alberto; Verstuyf, Annemieke

    Chemistry & Biology (Cambridge, MA, United States) (2008), 15 (10), 1029-1034CODEN: CBOLE2; ISSN:1074-5521. (Cell Press)

    Summary: Side chain fluorination is often used to make analogs of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] resistant to degrdn. by 24-hydroxylase. The fluorinated nonsteroidal analogs CD 578, WU 515, and WY 1113 have an increased prodifferentiating action on SW480-ADH colon cancer cells, which correlated with stronger induction of vitamin D receptor (VDR)-coactivator interactions and stronger repression of β-catenin/TCF activity. Cocrystn. of analog CD 578 with the zebrafish (z)VDR and an SRC-1 coactivator peptide showed that the fluorine atoms of CD 578 make addnl. contacts with Val444 and Phe448 of activation helix 12 (H12) of the zVDR and with Leu440 of the H11-H12 loop. Consequently, the SRC-1 peptide makes more contacts with the VDR-CD 578 complex than with the VDR-1,25(OH)2D3 complex. These data show that fluorination not only affects degrdn. of an analog but can also have direct effects on H12 stabilization.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXht1KmsrfJ&md5=198e333ec101e84677e974db0257d9d3

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    Huet, T. ; Maehr, H. ; Lee, H. ; Uskokovic, M. ; Suh, N. ; Moras, D. ; Rochel, N. Structure function study of Gemini derivatives with two different side chains at C-20, Gemini-0072 and Gemini-0097. MedChemComm 2011, 2 , 424– 429,  DOI: 10.1039/c1md00059d

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    138

    Structure-function study of gemini derivatives with two different side chains at C-20, Gemini-0072 and Gemini-0097

    Huet, Tiphaine; Maehr, Hubert; Lee, Hong Jin; Uskokovic, Milan R.; Suh, Nanjoo; Moras, Dino; Rochel, Natacha

    MedChemComm (2011), 2 (5), 424-429CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)

    Derivs. of vitamin D3 contg. a second side-chain emanating at C-20 are known as gemini and act as vitamin D receptor agonists. Recently, two of these, namely Gemini-0072 and the epimeric Gemini-0097, were selected for further studies in view of their high biol. activities and lack of hypercalcemic effects. The authors now show that the two analogs recruit coactivator SRC-1 better than the parental gemini and act as VDR superagonists. The crystal structures of complexes of zVDR with Gemini-0072 and Gemini-0097 indicate that these ligands induce an extra cavity within the ligand-binding pocket similar to gemini and that their superagonistic activity is due to an increased stabilization of helix H12.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXls1KhtL4%253D&md5=0e01899c367ef6925b6b1766e6d55ef3

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    Fischer, J. ; Wang, T. T. ; Kaldre, D. ; Rochel, N. ; Moras, D. ; White, J. H. ; Gleason, J. L. Synthetically accessible non-secosteroidal hybrid molecules combining vitamin D receptor agonism and histone deacetylase inhibition. Chem. Biol. 2012, 19 (8), 963– 971,  DOI: 10.1016/j.chembiol.2012.05.024

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    Synthetically Accessible Non-Secosteroidal Hybrid Molecules Combining Vitamin D Receptor Agonism and Histone Deacetylase Inhibition

    Fischer, Joshua; Wang, Tian-Tian; Kaldre, Dainis; Rochel, Natacha; Moras, Dino; White, John H.; Gleason, James L.

    Chemistry & Biology (Oxford, United Kingdom) (2012), 19 (8), 963-971CODEN: CBOLE2; ISSN:1074-5521. (Elsevier Ltd.)

    1,25-Dihydroxyvitamin D3 (1,25D), the hormonal form of vitamin D, and several analogs have failed as monotherapies for cancer because of poor efficacy or acquired resistance. However, 1,25D analogs are amenable to bifunctionalization. Preclin. studies have revealed combinatorial effects of 1,25D analogs and histone deacetylase inhibitors (HDACi). Secosteroidal hybrid mols. combining vitamin D receptor (VDR) agonism with HDACi displayed enhanced efficacy but are laborious to synthesize. Here, we have developed easily assembled, fully integrated, non-secosteroidal VDR agonist/HDACi hybrids. The most promising are full VDR agonists with ∼10-fold lower potency than 1,25D. Structure/function studies revealed that antiproliferative activity against 1,25D-resistant squamous carcinoma cells required VDR agonism and HDACi. Remarkably, modeling and X-ray crystallog. reveal non-secosteroidal hybrids bind in the VDR ligand binding domain in the opposite orientation of their secosteroidal counterparts.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1Krsr7O&md5=c2f4a5b98617eb68642d6a0fddadb6b4

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    Huet, T. ; Laverny, G. ; Ciesielski, F. ; Molnar, F. ; Ramamoorthy, T. G. ; Belorusova, A. Y. ; Antony, P. ; Potier, N. ; Metzger, D. ; Moras, D. ; Rochel, N. A vitamin D receptor selectively activated by Gemini analogs reveals ligand dependent and independent effects. Cell Rep. 2015, 10 (4), 516– 526,  DOI: 10.1016/j.celrep.2014.12.045

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    A Vitamin D Receptor Selectively Activated by Gemini Analogs Reveals Ligand Dependent and Independent Effects

    Huet, Tiphaine; Laverny, Gilles; Ciesielski, Fabrice; Molnar, Ferdinand; Ramamoorthy, Thanuja Gali; Belorusova, Anna Y.; Antony, Pierre; Potier, Noelle; Metzger, Daniel; Moras, Dino; Rochel, Natacha

    Cell Reports (2015), 10 (4), 516-526CODEN: CREED8; ISSN:2211-1247. (Cell Press)

    The bioactive form of vitamin D [1,25(OH)2D3] regulates mineral and bone homeostasis and exerts potent anti-inflammatory and antiproliferative properties through binding to the vitamin D receptor (VDR). The 3D structures of the VDR ligand-binding domain with 1,25(OH)2D3 or gemini analogs unveiled the mol. mechanism underlying ligand recognition. On the basis of structure-function correlations, we generated a point-mutated VDR (VDRgem) that is unresponsive to 1,25(OH)2D3, but the activity of which is efficiently induced by the gemini ligands. Moreover, we show that many VDR target genes are repressed by unliganded VDRgem and that mineral ion and bone homeostasis are more impaired in VDRgem mice than in VDR null mice, demonstrating that mutations abolishing VDR ligand binding result in more severe skeletal defects than VDR null mutations. As gemini ligands induce VDRgem transcriptional activity in mice and normalize their serum calcium levels, VDRgem is a powerful tool to further unravel both liganded and unliganded VDR signaling.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVeitro%253D&md5=403ce5ebb966a09137c35fe73d77646c

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    Belorusova, A. Y. ; Suh, N. ; Lee, H. J. ; So, J. Y. ; Maehr, H. ; Rochel, N. Structural analysis and biological activities of BXL0124, a Gemini analog of vitamin D. J. Steroid Biochem. Mol. Biol. 2017, 173 , 69– 74,  DOI: 10.1016/j.jsbmb.2016.09.015

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    Structural analysis and biological activities of BXL0124, a gemini analog of vitamin D

    Belorusova, Anna Y.; Suh, Nanjoo; Lee, Hong Jin; So, Jae Young; Maehr, Hubert; Rochel, Natacha

    Journal of Steroid Biochemistry and Molecular Biology (2017), 173 (), 69-74CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier Ltd.)

    Gemini analogs of calcitriol, characterized by the extension of the C21-Me group of calcitriol with a second chain, act as agonists of the vitamin D receptor (VDR). This second side chain of gemini is accommodated in a new cavity inside the VDR created by the structural rearrangement of the protein core. The resulting conformational change preserves the active state of the receptor and bestows gemini compds. with biol. activities that exceed those of calcitriol. Of particular interest are gemini's anti-cancer properties, and in this study we demonstrate anti-proliferative and tumor-reducing abilities of BXL0124 and BXL0097, differing only by the presence or absence, resp., of the methylene group on the A ring. BXL0124 acts as a more potent VDR agonist than its 19-nor counterpart by activating VDR-mediated transcription at lower concns. In a similar manner, BXL0124 is more active than BXL0097 in growth inhibition of breast cancer cells and redn. of tumor vol. Structural comparisons of BXL0097 and BXL0124, as their VDR complexes, explain the elevated activity of the latter.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslCgu7rE&md5=60dc1b3b18a83aae123af7bcb408c0ad

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    Lin, Z. ; Chen, H. ; Belorusova, A. Y. ; Bollinger, J. C. ; Tang, E. K. Y. ; Janjetovic, Z. ; Kim, T. K. ; Wu, Z. ; Miller, D. D. ; Slominski, A. T. ; Postlethwaite, A. E. ; Tuckey, R. C. ; Rochel, N. ; Li, W. 1α,20S-Dihydroxyvitamin D3 interacts with vitamin D receptor: Crystal structure and route of chemical synthesis. Sci. Rep. 2017, 7 (1), 10193,  DOI: 10.1038/s41598-017-10917-7

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    142

    1α,20S-Dihydroxyvitamin D3 Interacts with Vitamin D Receptor: Crystal Structure and Route of Chemical Synthesis

    Lin Zongtao; Chen Hao; Wu Zhongzhi; Miller Duane D; Li Wei; Belorusova Anna Y; Rochel Natacha; Belorusova Anna Y; Bollinger John C; Tang Edith K Y; Tuckey Robert C; Janjetovic Zorica; Kim Tae-Kang; Slominski Andrzej T; Slominski Andrzej T; Postlethwaite Arnold E; Postlethwaite Arnold E

    Scientific reports (2017), 7 (1), 10193 ISSN:.

    1α,20S-Dihydroxyvitamin D3 [1,20S(OH)2D3], a natural and bioactive vitamin D3 metabolite, was chemically synthesized for the first time. X-ray crystallography analysis of intermediate 15 confirmed its 1α-OH configuration. 1,20S(OH)2D3 interacts with the vitamin D receptor (VDR), with similar potency to its native ligand, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] as illustrated by its ability to stimulate translocation of the VDR to the nucleus, stimulate VDRE-reporter activity, regulate VDR downstream genes (VDR, CYP24A1, TRPV6 and CYP27B1), and inhibit the production of inflammatory markers (IFNγ and IL1β). However, their co-crystal structures revealed differential molecular interactions of the 20S-OH moiety and the 25-OH moiety to the VDR, which may explain some differences in their biological activities. Furthermore, this study provides a synthetic route for the synthesis of 1,20S(OH)2D3 using the intermediate 1α,3β-diacetoxypregn-5-en-20-one (3), and provides a molecular and biological basis for the development of 1,20S(OH)2D3 and its analogs as potential therapeutic agents.

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    Belorusova, A. Y. ; Martinez, A. ; Gandara, Z. ; Gomez, G. ; Fall, Y. ; Rochel, N. Structure-activity relationship study of vitamin D analogs with oxolane group in their side chain. Eur. J. Med. Chem. 2017, 134 , 86– 96,  DOI: 10.1016/j.ejmech.2017.03.081

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    143

    Structure-activity relationship study of vitamin D analogs with oxolane group in their side chain

    Belorusova, Anna Y.; Martinez, Andrea; Gandara, Zoila; Gomez, Generosa; Fall, Yagamare; Rochel, Natacha

    European Journal of Medicinal Chemistry (2017), 134 (), 86-96CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)

    Synthetic analogs of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) have been developed with the goal of improving the biol. profile of the natural hormone for therapeutic applications. Derivs. of 1,25(OH)2D3 with the oxolane moiety branched in the side chain at carbon C20, act as Vitamin D nuclear Receptor (VDR) superagonists being several orders of magnitude more active than the natural ligand. Here, the authors describe the synthesis and biol. evaluation of three diastereoisomers of (1S, 3R)-Dihydroxy-(20S)-[(2''-hydroxy-2''-propyl)-tetrahydrofuryl]-22,23,24,25,26,27-hexanor-1α-hydroxyvitamin D3, with different stereochem. at positions C2 and C5 of the oxolane ring branched at carbon C22 (1, C2RC5S; 2, C2SC5R; 3, C2SC5S). These compds. act as weak VDR agonist in transcriptional assays with compd. 3 being the most active. X-ray crystallog. anal. of the VDR ligand-binding domain accommodating the three compds. indicates that the oxolane group branched at carbon C22 is not constrained as in case of compd. with oxolane group branched at C20 leading to the loss of interactions of the triene group and increased flexibility of the C/D-rings and of the side chain.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmvFWnt74%253D&md5=21b45f992e7c9a5216178c36c4f14ddc

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    Lin, Z. ; Marepally, S. R. ; Goh, E. S. Y. ; Cheng, C. Y. S. ; Janjetovic, Z. ; Kim, T. K. ; Miller, D. D. ; Postlethwaite, A. E. ; Slominski, A. T. ; Tuckey, R. C. ; Peluso-Iltis, C. ; Rochel, N. ; Li, W. Investigation of 20S-hydroxyvitamin D3 analogs and their 1α-OH derivatives as potent vitamin D receptor agonists with anti-inflammatory activities. Sci. Rep. 2018, 8 (1), 1478,  DOI: 10.1038/s41598-018-19183-7

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    144

    Investigation of 20S-hydroxyvitamin D3 analogs and their 1α-OH derivatives as potent vitamin D receptor agonists with anti-inflammatory activities

    Lin Zongtao; Marepally Srinivasa R; Miller Duane D; Li Wei; Lin Zongtao; Goh Emily S Y; Cheng Chloe Y S; Tuckey Robert C; Janjetovic Zorica; Kim Tae-Kang; Slominski Andrzej T; Postlethwaite Arnold E; Postlethwaite Arnold E; Slominski Andrzej T; Peluso-Iltis Carole; Rochel Natacha

    Scientific reports (2018), 8 (1), 1478 ISSN:.

    20S-hydroxyvitamin D3 [20S(OH)D3] is anti-inflammatory and not hypercalcemic, suggesting its potential as a lead compound. In this study, side chain modified 20S(OH)D3 analogs (4, 13, 23 and 33) together with their 1α-OH derivatives were synthesized and their metabolism and biological activities tested. 4, 13 and 23 are good substrates for CYP27B1, enabling enzymatic synthesis of their 1α-OH derivatives 5, 14 and 24. However, 33 could not be hydroxylated by CYP27B1 and acts as an inhibitor. All analogs were poorer substrates for CYP24A1 than calcitriol, indicating improved catabolic stability. While the parent analogs showed minimal VDR stimulating activity, their 1α-OH derivatives were potent VDR agonists. 4, 5, 14 and 24 significantly upregulated the expression of CYP24A1 at the mRNA level, consistent with their VDR activation abilities and indicating that 1α-hydroxylation is required to produce analogs with strong activity. These analogs have anti-inflammatory activities that are influenced by side chain composition and by 1α-hydroxylation. To understand their molecular interactions with the VDR, 20S(OH)D3, 4 and 33 were co-crystalized with the VDR ligand binding domain, which revealed subtle differences to the calcitriol-bound receptor. This study demonstrates the potential of the 20S(OH)D3 scaffold for the development of novel anti-inflammatory agents.

    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MvktVyjtg%253D%253D&md5=8f9302ab65a76a1dc5a9a0475ffacd77

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Natural Vitamin D Vs Synthetic Vitamin D

Source: https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b00208