Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
Department of Chemistry, Faculty of Science, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan.
Bioorg Med Chem. 2019 Aug 15;27(16):3674-3681. doi: 10.1016/j.bmc.2019.07.003. Epub 2019 Jul 3.
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 D, 1α,25-dihydroxyvitamin D (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.
胆酸（2）被鉴定为维生素 D 受体（VDR）的第二个内源性配体，尽管其与 VDR 的结合亲和力及其维生素 D 活性与维生素 D 的活性代谢物 1α，25-二羟基维生素 D（1）相比非常弱。据报道，3-酰化胆酸作为 VDR 激动剂比胆酸（2）略有效。在这里，为了开发更有效的胆酸衍生物，我们合成了几种带有 3-磺酸酯/碳酸酯或 3-氨基/酰胺取代基的衍生物，并研究了它们对人早幼粒细胞白血病 HL-60 细胞的诱导分化活性。在胆酸（2）的 3-位引入氮原子会降低活性，但带有 3-甲磺酸盐基团的化合物 6 的活性比胆酸（2）或其酰化衍生物更强。通过竞争性结合测定和 VDR 配体结合域（LBD）与 6 的复合物的 X 射线晶体学分析证实了 6 与 VDR 的结合。
