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, Hitoshi; Tokiwa, Hiroaki; Ikura, Teikichi; Ito, Nobuyasu; Makishima, Makoto; Yamada, Sachiko

doi:10.1021/jm401989c

Cited by 23 publications

(48 citation statements)

References 47 publications

(97 reference statements)

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“…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 …”

Section: Discussionmentioning

confidence: 89%

Vitamin D and Its Synthetic Analogs

2019

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For many individuals, in particular during winter, supplementation with the secosteroid vitamin D 3 is essential for the prevention of bone disorders, muscle weakness, autoimmune diseases, and possibly also different types of cancer. Vitamin D 3 acts via its metabolite 1α,25-dihydroxyvitamin D 3 [ 1,25(OH) 2 D 3 ] as potent agonist of the transcription factor vitamin D receptor (VDR). Thus, vitamin D directly affects chromatin structure and gene regulation at thousands of genomic loci, i.e., the epigenome and transcriptome of its target tissues. Modifications of 1,25(OH) 2 D 3 at its side-chain, A-ring, triene system, or C-ring, alone and in combination, as well as nonsteroidal mimics provided numerous potent VDR agonists and some antagonists. The nearly 150 crystal structures of VDR’s ligand-binding domain with various vitamin D compounds allow a detailed molecular understanding of their action. This review discusses the most important vitamin D analogs presented during the past 10 years and molecular insight derived from new structural information on the VDR protein.

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“…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 …”

Section: Discussionmentioning

confidence: 89%

Vitamin D and Its Synthetic Analogs

2019

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“…Next, we examined the VDR trasactivation ability for selected compounds ( Figure 4 and Table 1 ), according to the method reported in our previous study [ 13 ]. 1α,25(OH) 2 D 3 ( 1 , EC 50 : 0.058 nM) and compound 3 ( Dcha-20 , EC 50 : 0.083 nM) showed potent transactivation activity at the concentrations above 0.1 nM, while LCA ( 2 ) did not show the activity at the concentration below 1 μ M. All the amide derivatives examined showed dose-dependent transactivation activity, which was well correlated with the activity in HL-60 cell assay.…”

Section: Resultsmentioning

confidence: 99%

“…Human embryonic kidney HEK293 cells (RIKEN Cell Bank, Tsukuba, Japan) were cultured in Dulbecco’s modified Eagle’s medium containing 5% FBS, 100 U/mL penicillin, and 0.1 mg/mL streptomycin (Nacalai Tesque, Kyoto, Japan). Transfections used 15 ng of pCMX-hVDR, 50 ng of TK-Spp × 3-LUC reporter plasmid, and 10 ng of pCMX-β-galactosidase for each well of a 96-well plate, and were performed by the calcium phosphate coprecipitation assay as described previously [ 13 ]. Eight hours after transfection, test compounds were added.…”

Section: Methodsmentioning

confidence: 99%

Lithocholic Acid Amides as Potent Vitamin D Receptor Agonists

et al. 2022

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1α,25-Dihydroxyvitamin D3 [1α,25(OH)2D3, 1] is an active form of vitamin D3 and regulates various biological phenomena, including calcium and phosphate homeostasis, bone metabolism, and immune response via binding to and activation of vitamin D receptor (VDR). Lithocholic acid (LCA, 2) was identified as a second endogenous agonist of VDR, though its potency is very low. However, the lithocholic acid derivative 3 (Dcha-20) is a more potent agonist than 1α,25(OH)2D3, (1), and its carboxyl group has similar interactions to the 1,3-dihydroxyl groups of 1 with amino acid residues in the VDR ligand-binding pocket. Here, we designed and synthesized amide derivatives of 3 in order to clarify the role of the carboxyl group. The synthesized amide derivatives showed HL-60 cell differentiation-inducing activity with potency that depended upon the substituent on the amide nitrogen atom. Among them, the N-cyanoamide 6 is more active than either 1 or 3.

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“…In THP-1 cells, ADTT and ADMI3 reduced the mRNA levels of CYP1A1 in the presence of 1,25-(OH) 2 D 3 and benzo[a]pyrene (an aryl hydrocarbon agonist) (156). A recent series of ADTK1-4 analogs exhibited significantly less antagonist activity than ADTT (157). …”

Section: Vdr Antagonists or Allosteric Inhibition Of The Vdr–coregmentioning

confidence: 99%

Inhibitors for the Vitamin D Receptor–Coregulator Interaction

Teske

2016

Vitamin D Hormone

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The vitamin D receptor (VDR) belongs to the superfamily of nuclear receptors and is activated by the endogenous ligand 1,25-dihydroxyvitamin D3. The genomic effects mediated by VDR consist of the activation and repression of gene transcription, which includes the formation of multi-protein complexes with coregulator proteins. Coregulators bind many nuclear receptors and can be categorized according their role as coactivators (gene activation) or corepressors (gene repression). Herein, different approaches to develop compounds that modulate the interaction between VDR and coregulators are summarized. This include coregulator peptides that were identified by creating phage display libraries. Subsequent modification of these peptides including the introduction of a tether or non-hydrolysable bonds resulted in the first direct VDR–coregulator inhibitors. Later, small molecules that inhibit VDR–coregulator inhibitors were identified using rational drug design and high throughput screening. Early on, allosteric inhibition of VDR–coregulator interactions was achieved with VDR antagonists that change the conformation of VDR and modulate the interactions with coregulators. A detailed discussion of their dual agonist/antagonist effects is given as well as a summary of their biological effects in cell-based assays and in vivo studies.

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

Cited by 23 publications

References 47 publications

Vitamin D and Its Synthetic Analogs

Vitamin D and Its Synthetic Analogs

Lithocholic Acid Amides as Potent Vitamin D Receptor Agonists

Inhibitors for the Vitamin D Receptor–Coregulator Interaction

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