Synthesis of C-2 substituted vitamin D derivatives having ringed side chains and their biological evaluation, especially biological effect on bone by modification at the C-2 position

Org Biomol Chem. 2011 May 21;9(10):3954-64. doi: 10.1039/c1ob05142c. Epub 2011 Apr 7.

Abstract

In order to obtain vitamin D derivatives, which have strong activity for enhancing bone growth, we designed vitamin D derivatives with various substitutions at the C-2 position. Novel 2 α-substituted vitamin D derivatives were synthesized starting from d-glucose as a chiral template of the A-ring with a CD-ring bromoolefin unit using the Trost coupling method. We evaluated these compounds by two in vitro assays, affinity to VDR and transactivation assays, using human osteosarcoma (Hos) cells, and demonstrated the SAR of the C-2 position of VD(3). Furthermore, by using the OVX model, we found that compound 5c, which has a hydroxypropoxy side chain at C-2 and 2,2-dimethyl cyclopentanone in the CD-ring side chain, has a strong activity for enhancing bone growth, same as the reported compound, 2α-(3-hydroxypropoxy)-1α,25-dihydroxyvitamin D(3)1d, and this derivative shows a possibility that calcemic activity is less than 1d in vivo.

MeSH terms

  • Animals
  • Bone Density / drug effects
  • Bone and Bones / drug effects*
  • Bone and Bones / physiology
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Drug Design
  • Female
  • Humans
  • Ovariectomy
  • Rats
  • Receptors, Calcitriol / metabolism
  • Structure-Activity Relationship
  • Transcriptional Activation / drug effects
  • Vitamin D / analogs & derivatives
  • Vitamin D / chemical synthesis*
  • Vitamin D / metabolism
  • Vitamin D / pharmacology*

Substances

  • Receptors, Calcitriol
  • Vitamin D