1α,20S-Dihydroxyvitamin D Interacts with Vitamin D Receptor: Crystal Structure and Route of Chemical Synthesis

Academic Article

Abstract

  • © 2017 The Author(s). 1α,20S-DihydroxyVitamin D3 [1,20S(OH)2D3], a natural and bioactive Vitamin D3 metabolite, was chemically synthesized for the first time. X-ray crystallography analysis of intermediate 15 confirmed its 1α-OH configuration. 1,20S(OH)2D3 interacts with the Vitamin D receptor (VDR), with similar potency to its native ligand, 1α,25-dihydroxyVitamin D3 [1,25(OH)2D3] as illustrated by its ability to stimulate translocation of the VDR to the nucleus, stimulate VDRE-reporter activity, regulate VDR downstream genes (VDR, CYP24A1, TRPV6 and CYP27B1), and inhibit the production of inflammatory markers (IFNγ and IL1β). However, their co-crystal structures revealed differential molecular interactions of the 20S-OH moiety and the 25-OH moiety to the VDR, which may explain some differences in their biological activities. Furthermore, this study provides a synthetic route for the synthesis of 1,20S(OH)2D3 using the 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.
  • Published In

  • Scientific Reports  Journal
  • Digital Object Identifier (doi)

    Pubmed Id

  • 21571321
  • Author List

  • Lin Z; Chen H; Belorusova AY; Bollinger JC; Tang EKY; Janjetovic Z; Kim TK; Wu Z; Miller DD; Slominski AT
  • Volume

  • 7
  • Issue

  • 1