1α,20S-Dihydroxyvitamin D3 [1,20S(OH)2D3], a natural and bioactive vitamin D3 metabolite, was chemically synthesized for the first time. A semi-reduced intermediate (14a) of the Birch reduction during 1α-OH formation was obtained, and was used to propose the reaction mechanism. X-ray crystallography analysis of intermediate 15 confirmed its 1α-OH configuration. 1,20S(OH)2D3 binds efficiently to vitamin D receptor (VDR), with similar affinity with its native ligand 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3]. However, their co-crystal structures revealed differential molecular interactions of the 20S-OH moiety and the 25-OH moiety to the VDR, which may help explain their biological activities. In addition, 1,20S(OH)2D3 functions as a VDR agonist with comparable activities to 1,25(OH)2D3 with respect to of VDR stimulation, VDR translocation, regulation of VDR downstream genes (VDR, CYP24A1, TRPV6 and CYP27B1), and inhibition of inflammatory markers (IFNγ and IL1α). This study offers a convenient synthetic route using a novel intermediate 1α,3β-diacetoxypregn-5-en-20-one (3), and provides a molecular and biological basis for the development of 1,20S(OH)2D3 and its analogs as potential therapeutic agents.

Synthesis of natural 1α,20S-dihydroxyvitamin D3 as a potent vitamin D receptor agonist and anti-inflammatory agent

254th National Meeting (2017)

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