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, Nobuyasu

doi:10.1016/j.bmc.2008.05.043

Cited by 50 publications

(63 citation statements)

References 31 publications

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“…In the present study, we observed clear electron density in the LBP, as was previously reported in the complex with 1,25(OH) 2 D 3 ( Fig. 3A ) ( 28 ), and crystallographic refi nement allowed us unambiguous determination of the structure of LCA and its derivatives in the complex ( Figs. 2A and 3A ).…”

Section: Structures Of the Ligands And Their Interactions With Vdr-ldbsupporting

confidence: 88%

“…Two more residues at the C-terminal end (Glu421 and Ile422) were also undetectable in the complexes with LCA and 3-keto LCA. Most of these missing residues were previously reported as invisible in studies of other ternary complexes of VDR and are likely a characteristic common to crystals of VDR complexes (23)(24)(25)(26)(27)(28)(29)(30)(31).…”

Section: Structures Of the Ligands And Their Interactions With Vdr-ldbmentioning

confidence: 91%

“…1 ) to investigate how LCA and its derivatives bind to VDR and how they act as the agonists. The structures reveal that LCA and its derivatives bind to the same ligand-binding pocket (LBP) of VDR that 1,25(OH) 2 D 3 binds to (23)(24)(25)(26)(27)(28)(29)(30)(31), but in the opposite orientation. Comparison of these structures also show how LCA and its derivatives mimic 1,25(OH) 2 D 3 and give insight into how the C-3 substituents on the A-ring affect the activity of each ligand.…”

Section: Overall Structures Of the Ternary Complexesmentioning

confidence: 99%

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

Masuno

Ikura

Morizono

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org super family ( 15 ). When 1,25(OH) 2 D 3 is bound to VDR, it activates it by inducing conformational changes. The activated complex, VDR/1,25(OH) 2 D 3 , binds as a heterodimer with the retinoid X receptor (RXR) to vitamin D response elements located in the promoter region of the target genes. Recruitment of coactivator proteins to this heterodimer is also essential to the transactivation. However, clinical use of 1,25(OH) 2 D 3 is limited because therapeutic doses can give rise to signifi cant hypercalciuria and hypercalcemia ( 16 ). A number of synthetic ligands to VDR have been developed for medical use; however, most of them can also cause similar problems because they are derived from 1,25(OH) 2 D 3 .Several synthetic compounds without the vitamin D 3 scaffold have been reported to bind to VDR and have VDR-modulating activities, including growth inhibition of cancer cells and keratinocytes and induction of leukemic cell differentiation, with less calcium mobilization side effects than 1,25(OH) 2 D 3 ( 17 ). Therefore, these synthetic compounds are expected to be therapeutics for cancer, leukemia, and psoriasis. Subsequently, Makishima et al. discovered that secondary bile acids, including lithocholic acid (LCA) and its derivatives, also behaved as VDR agonists (18)(19)(20). LCA acts as a detergent to stabilize fats for absorption, and it has been implicated in human and experimental animal carcinogenesis. However, the agonistic behavior of LCA as a ligand recognized by VDR was not common knowledge because the structure of LCA is completely different from that of vitamin D 3 . Additional studies showed that VDR had dual functions as a metabolic sensor of bile acids and as an endocrine receptor for 1,25(OH) 2 D 3 . , regulates calcium homeostasis ( 1 ). It also promotes cellular differentiation, inhibits cellular proliferation, and suppresses the immune system ( 2-7 ). It has been used clinically to treat renal osteodystrophy, vitamin D-dependent rickets type I, and X-linked hypophosphatemic rickets, among other conditions (8)(9)(10)(11)(12)(13)(14). Most of its effects are mediated by its specifi c binding to the vitamin D receptor (VDR), which is a member of nuclear receptor (NR) Abstract Manuscript

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Section: Structures Of the Ligands And Their Interactions With Vdr-ldbsupporting

confidence: 88%

Section: Structures Of the Ligands And Their Interactions With Vdr-ldbmentioning

confidence: 91%

Section: Overall Structures Of the Ternary Complexesmentioning

confidence: 99%

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

Masuno

Ikura

Morizono

et al. 2013

Journal of Lipid Research

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“…Analogs (20S and 20R) bearing 2b-hydroxyethoxy group together with other modifications (16ene-22thia-19nor and C26 and C27 methylation) have been crystallized in complex with rVDRD and Drip205 coactivator peptide [26]. The 20S isomer acts as VDR superagonist [51]. The 2b-hydroxyethoxy group in the 20S or 20R complex shows further stabilizing interactions via hydrogen bonds between the terminal OH moiety of the 2-substituent and both Arg270 (hArg274) and a water molecule.…”

Section: Structures Of Vdr Complexed To 2a-substituted Analogsmentioning

confidence: 99%

“…Several crystal structures of the VDR ligand-binding domain bound to selected C-2a substituted analogs that fill this water channel have been described [26,50,51]. The crystal structures of hVDR in complexes with C-2a substituted analogs bearing methyl, propyl, propoxy, hydroxypropyl, and hydroxypropoxy groups on C-2a position were solved [50].…”

Section: Structures Of Vdr Complexed To 2a-substituted Analogsmentioning

confidence: 99%

Structural Basis for Ligand Activity in VDR

Rochel

Moras

2011

Vitamin D

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Recent Developments of 19‐Nor‐1,25‐dihydroxyvitamin D₃ Analogues

2013

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The vitamin D hormone, 1α,25-dihydroxyvitamin D3 [1,25-(OH)2 D3 ], exerts its hormonal effects predominantly on intestine, bone, and kidney, where it plays a crucial role in calcium and phosphorus homeostasis and bone mineralization. In addition to its classical actions, 1,25(OH)2 D3 exerts pleiotropic effects in a wide variety of target tissues and cell types, often in an autocrine/paracrine fashion. These biological activities of 1,25(OH)2 D3 have suggested a multitude of potential therapeutic applications for the vitamin D hormone in the treatment of hyperproliferative disorders (e.g. cancer and psoriasis), immune dysfunction (autoimmune diseases), and endocrine disorders (e.g. hyperparathyroidism). However, the calcemic effects induced by 1,25(OH)2 D3--hypercalcemia, increased bone resorption, and soft tissue calcification--limit the use of the natural ligand in these clinical applications. Therefore, numerous 1,25(OH)2 D3 analogues have been synthesized with the intent of producing therapeutic agents devoid of hypercalcemic and hyperphosphatemic side effects. To this aim, much attention has been focused on the development of 19-nor-vitamin D3 derivatives that lack the ring-A exocyclic methylene group (C19). In this review, the 19-nor-1,25(OH)2 D3 analogues are classified according to modifications made at the A-ring, the side chain, or both the A-ring and side chain, as well as other positions. The biological activities of these 19-nor-1,25(OH)2 D3 analogues are summarized and their structure-activity relationships and binding features with the vitamin D receptor (VDR) are discussed.

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

Cited by 50 publications

References 31 publications

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

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

Structural Basis for Ligand Activity in VDR

Recent Developments of 19‐Nor‐1,25‐dihydroxyvitamin D₃ Analogues

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

Cited by 50 publications

References 31 publications

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

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

Structural Basis for Ligand Activity in VDR

Recent Developments of 19‐Nor‐1,25‐dihydroxyvitamin D3 Analogues

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Recent Developments of 19‐Nor‐1,25‐dihydroxyvitamin D₃ Analogues