Design, Synthesis, Biological Activity, and Structural Analysis of Novel Des-C-Ring and Aromatic-D-Ring Analogues of 1α,25-Dihydroxyvitamin D3

J Med Chem. 2022 Oct 13;65(19):13112-13124. doi: 10.1021/acs.jmedchem.2c00900. Epub 2022 Sep 27.


The toxic calcemic effects of the natural hormone 1α,25-dihydroxyvitamin D3 (1,25D3, 1,25-dihydroxycholecalciferol) in the treatment of hyperproliferative diseases demand the development of highly active and noncalcemic vitamin D analogues. We report the development of two highly active and noncalcemic analogues of 1,25D3 that lack the C-ring and possess an m-phenylene ring that replaces the natural D-ring. The new analogues (3a, 3b) are characterized by an additional six-carbon hydroxylated side chain attached either to the aromatic nucleus or to the triene system. Both compounds were synthesized by the Pd-catalyzed tandem cyclization/cross coupling approach starting from alkyne 6 and diphenol 8. Key steps include a stereoselective Cu-assisted addition of a Grignard reagent to an aromatic alkyne and a Takai olefination of an aromatic aldehyde. The new compounds are noncalcemic and show transcriptional and antiproliferative activities similar to 1,25D3. Structural analysis revealed that they induce a large conformational rearrangement of the vitamin D receptor around helix 6.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehydes
  • Alkynes / pharmacology
  • Calcitriol* / pharmacology
  • Carbon
  • Hormones
  • Palladium / chemistry
  • Receptors, Calcitriol*
  • Vitamin D / analogs & derivatives


  • Aldehydes
  • Alkynes
  • Hormones
  • Receptors, Calcitriol
  • Vitamin D
  • Palladium
  • 1,25-dihydroxyvitamin D
  • Carbon
  • Calcitriol