D-seco-Vitamin D analogs having reversed configurations at C-13 and C-14: Synthesis, docking studies and biological evaluation

Abstract

Prompted by results of molecular modeling performed on the seco-d-ring-vitamins D, we turned our attention to such analogs, having reversed configurations at C-13 and C-14, as the next goals of our studies on the structure-activity relationship for vitamin D compounds. First, we developed an efficient total synthesis of the “upper” C/seco-d-ring fragment with a 7-carbon side chain. Then, we coupled it with A-ring fragments using Sonogashira or Wittig-Horner protocol, providing the targeted D-seco analogs of 1α,25-dihydroxyvitamin D3 and 1α,25-dihydroxy-19-norvitamin D3 possessing a vinyl substituent at C-14 and a double bond between C-17 and C-20.The affinities of the synthesized vitamin D analogs to the full-length recombinant rat VDR were examined, as well as their differentiating and transcriptional activities. In these in vitro tests, they were significantly less active compared to 1α,25-(OH)2D3. Moreover, it was established that the analogs tested in vivo in rats showed no calcemic potency.