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Development of Novel Lithocholic Acid Derivatives as Vitamin D Receptor Agonists

Development of Novel Lithocholic Acid Derivatives as Vitamin D Receptor Agonists

Hiroyuki Masuno, Yuko Kazui, Aya Tanatani, Shinya Fujii, Emiko Kawachi, Teikichi Ikura, Nobutoshi Ito, Keiko Yamamoto, Hiroyuki Kagechika

Bioorg Med Chem. 2019 Aug 15;27(16):3674-3681.

PMID: 31300316

Abstract:

Lithocholic acid (2) was identified as the second endogenous ligand of vitamin D receptor (VDR), though its binding affinity to VDR and its vitamin D activity are very weak compared to those of the active metabolite of vitamin D3, 1α,25-dihydroxyvitamin D3 (1). 3-Acylated lithocholic acids were reported to be slightly more potent than lithocholic acid (2) as VDR agonists. Here, aiming to develop more potent lithocholic acid derivatives, we synthesized several derivatives bearing a 3-sulfonate/carbonate or 3-amino/amide substituent, and examined their differentiation-inducing activity toward human promyelocytic leukemia HL-60 cells. Introduction of a nitrogen atom at the 3-position of lithocholic acid (2) decreased the activity, but compound 6 bearing a 3-methylsulfonate group showed more potent activity than lithocholic acid (2) or its acylated derivatives. The binding of 6 to VDR was confirmed by competitive binding assay and X-ray crystallographic analysis of the complex of VDR ligand-binding domain (LBD) with 6.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP434139-A	Lithocholic acid		434-13-9	Price

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