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Lithocholic Acid Amides as Potent Vitamin D Receptor Agonists.


ABSTRACT: 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.

SUBMITTER: Yoshihara A 

PROVIDER: S-EPMC8773473 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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1α,25-Dihydroxyvitamin D<sub>3</sub> [1α,25(OH)<sub>2</sub>D<sub>3</sub>, <b>1</b>] is an active form of vitamin D<sub>3</sub> 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, <b>2</b>) was identified as a second endogenous agonist of VDR, though its potency is very low. However, the lithocholic acid derivative <b>3</b> (<b>Dcha-20</b>) is  ...[more]

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