25 S-Adamantyl-23-yne-26,27-dinor-1α,25-dihydroxyvitamin D3: Synthesis, Tissue Selective Biological Activities, and X-ray Crystal Structural Analysis of Its Vitamin D Receptor Complex

J Med Chem. 2018 Aug 9;61(15):6658-6673. doi: 10.1021/acs.jmedchem.8b00427. Epub 2018 Jul 23.


Both 25 R- and 25 S-25-adamantyl-23-yne-26,27-dinor-1α,25-dihydroxyvitamin D3 (4a and 4b) were stereoselectively synthesized by a Pd(0)-catalyzed ring closure and Suzuki-Miyaura coupling between enol-triflate 7 and alkenyl-boronic ester 8. The 25 S isomer (4b) showed high vitamin D receptor (VDR) affinity (50% of that of the natural hormone 1α,25-dihydroxyvitamin D3, 1) and transactivation potency (kidney HEK293, 90%). In endogenous gene expression, it showed high cell-type selectivity for kidney cells (HEK293, CYP24A1 160% of 1), bone cells (MG63, osteocalcin 64%), and monocytes (U937, CAMP 96%) over intestine (SW480, CYP24A1 8%) and skin (HaCaT, CYP24A1 7%) cells. The X-ray crystal structural analysis of 4b in complex with rat VDR-ligand binding domain (LBD) showed the highest Cα positional shift from the 1/VDR-LBD complex at helix 11. Helix 11 of the 4b and 1 VDR-LBD complexes also showed significant differences in surface properties. These results suggest that 4b should be examined further as another candidate for a mild preventive osteoporosis agent.

MeSH terms

  • Biological Transport
  • Chemistry Techniques, Synthetic
  • Crystallography, X-Ray
  • HEK293 Cells
  • Humans
  • Receptors, Calcitriol / chemistry*
  • Receptors, Calcitriol / genetics
  • Receptors, Calcitriol / metabolism*
  • Stereoisomerism
  • Transcription, Genetic / drug effects
  • Vitamin D / analogs & derivatives*
  • Vitamin D / chemical synthesis
  • Vitamin D / chemistry
  • Vitamin D / metabolism
  • Vitamin D / pharmacology


  • Receptors, Calcitriol
  • Vitamin D
  • 1,25-dihydroxyvitamin D