Synthesis and in vitro evaluation of side chain-unsaturated analogs of 24a,24b-dihomo-1,25-dihydroxycholecalciferol

Abstract A synthesis and an in vitro evaluation of side chain-unsaturated analogs 3 and 4 of 24a,24b-dihomo-1,25-dihydroxycholecalciferol ( 1 ) are described. Novel C 23a,24 -vitamin D synthons (sulfone 10 and aldehyde 11 ) were used for the synthesis of analog 4 and for the efficient preparation of the parent compound 1 . The synthetic approach developed allows the use of easily available side chain fragments, such as oxirane 12 or Witting reagent 15 for the preparation of compound 1 and analog 4 , respectively. Introduction of a 4a E double bond results in a selective, 1000-fold increase in the binding affinity of analog 4 for the vitamin D receptor, compared to the affinity of 1 , whereas the affinity of 4 for the vitamin D-binding protein and the activity in stimulating the differentiation of human promyelocytic leukemia HL-60 cells remained largely unchanged.