Synthesis and biological evaluation of 1α,25-dihydroxyvitamin D₃ analogues with a long side chain at C12 and short C17 side chains

J Med Chem. 2012 Oct 25;55(20):8642-56. doi: 10.1021/jm3008272. Epub 2012 Oct 4.


Structure-guided optimization was used to design new analogues of 1α,25-dihydroxyvitamin D₃ bearing the main side chain at C12 and a shorter second hydroxylated chain at C17. The new compounds 5a-c were efficiently synthesized from ketone 9 (which is readily accessible from the Inhoffen-Lythgoe diol) with overall yields of 15%, 6%, and 3% for 5a, 5b, and 5c, respectively. The triene system was introduced by the Pd-catalyzed tandem cyclization-Suzuki coupling method. The new analogues were assayed against human colon and breast cancer cell lines and in mice. All new vitamin D₃ analogues bound less strongly to the VDR than 1α,25-dihydroxyvitamin D₃ but had similar antiproliferative, pro-differentiating, and transcriptional activity as the native hormone. In vivo, the three analogues had markedly low calcemic effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology
  • Cadherins / metabolism
  • Calcitriol / analogs & derivatives*
  • Calcitriol / chemical synthesis*
  • Calcitriol / pharmacology
  • Calcium / blood
  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cystatins / metabolism
  • Drug Screening Assays, Antitumor
  • Female
  • Humans
  • Mice
  • Molecular Docking Simulation
  • Receptors, Calcitriol / metabolism
  • Structure-Activity Relationship
  • Transcription, Genetic / drug effects


  • Antineoplastic Agents
  • Cadherins
  • Cystatins
  • Receptors, Calcitriol
  • CST5 protein, human
  • Calcitriol
  • Calcium