Chemical Synthesis and Biological Activities of 20S,24S/R-Dihydroxyvitamin D3 Epimers and Their 1α-Hydroxyl Derivatives

J Med Chem. 2015 Oct 8;58(19):7881-7. doi: 10.1021/acs.jmedchem.5b00881. Epub 2015 Sep 28.

Abstract

Bioactive vitamin D3 metabolites 20S,24S-dihydroxyvitamin D3 [20S,24S(OH)2D3] and 20S,24R-dihydroxyvitamin D3 [20S,24R(OH)2D3] were chemically synthesized and confirmed to be identical to their enzymatically generated counterparts. The absolute configurations at C24 and its influence on the kinetics of 1α-hydroxylation by CYP27B1 were determined. Their corresponding 1α-hydroxyl derivatives were subsequently produced. Biological comparisons of these products showed different properties with respect to vitamin D3 receptor activation, anti-inflammatory activity, and antiproliferative activity, with 1α,20S,24R(OH)2D3 being the most potent compound.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase / metabolism
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Caco-2 Cells / drug effects
  • Chemistry Techniques, Synthetic
  • Drug Evaluation, Preclinical / methods
  • Humans
  • Hydroxylation
  • Interferon-gamma / antagonists & inhibitors*
  • Isomerism
  • Magnetic Resonance Spectroscopy
  • Mice, Inbred DBA
  • Molecular Structure
  • Receptors, Calcitriol / genetics
  • Receptors, Calcitriol / metabolism*
  • Receptors, Immunologic / metabolism
  • Vitamin D / analogs & derivatives*
  • Vitamin D / chemistry

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Receptors, Calcitriol
  • Receptors, Immunologic
  • dihydroxy-vitamin D3
  • leukocyte-associated immunoglobulin-like receptor 1
  • Vitamin D
  • Interferon-gamma
  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase