Synthesis of 2α- and 2β-(3-hydroxypropyl)- 7,8-cis-14-epi-1α,25-dihydroxy-19-norvitamin D3 and their biological activity

J Steroid Biochem Mol Biol. 2017 Oct:173:79-82. doi: 10.1016/j.jsbmb.2016.09.007. Epub 2016 Sep 11.

Abstract

According to the binding mode of 14-epi-1α,25-dihydroxy-19-nortachysterol in the ligand binding domain of human vitamin D receptor (hVDR), i.e., 5,6- and 7,8-s-trans configuration that was shown by X-ray co-crystallographic analysis, 7,8-cis-locked 1α,25(OH)2D3 analogs were synthesized. In this paper, the synthesis and biological activity of 2α- and 2β-(3-hydroxypropyl)-7,8-cis-14-epi-1α,25-dihydroxy-19-norvitamin D3 are reported. The A-ring and CD-ring precursors for the Julia-Kociensky coupling reaction to create a diene system of the target molecules were prepared using our original methods. hVDR binding affinity and osteocalcin promoter transactivation activity of the new 7,8-cis-14-epi-vitamin D3 analogs were evaluated. Interestingly, the 2β-substituted 7,8-cis-analog was a better binder for hVDR than the 2α-isomeric counterpart.

Keywords: 7,8-cis-19-norvitamin D(3) analog; Synthesis; Transactivation; VDR binding affinity; Vitamin D receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcitriol / analogs & derivatives*
  • Calcitriol / chemical synthesis
  • Calcitriol / chemistry
  • Calcitriol / pharmacology
  • Chemistry Techniques, Synthetic / methods
  • Humans
  • Protein Binding
  • Receptors, Calcitriol / metabolism*
  • Vitamins / chemical synthesis*
  • Vitamins / chemistry
  • Vitamins / pharmacology*

Substances

  • Receptors, Calcitriol
  • VDR protein, human
  • Vitamins
  • 1,25-dihydroxy-19-norvitamin D3
  • Calcitriol