Conformationally restricted hybrid analogues of the hormone 1α,25-dihydroxyvitamin D₃: Design, synthesis, and biological evaluation

Four new conformationally restricted hybrid analogues of the hormone 1α-25-dihydroxyvitamin D₃ (1,25D3) have been synthesized in a convergent manner by combining enantiomerically pure C,D-ring ketones ( - )-15 and ( - )-17 with racemic 1-hydroxymethyl A-ring phosphine oxide (±)-18. Parent hybrid analogue 6, which combines the calcemia-inactivating 1β-hydroxymethyl A-ring modification with the antiproliferation- activating 20-epi-22-oxa-25-hydroxydiethyl C,D-ring side chain modification, is comparable in potency to 1,25D3 at the low nM level in inhibiting proliferation in a wide assortment of malignant cell lines in vitro with extremely low calcemic activity in vivo. Surprisingly, both conformationally, restricted analogues of 6 (8b and 9b), which incorproate rigidifying units at their 25-hydroxyl side chain termini, retained the desirable antiproliferative, transcriptional, and calcemic activities of the parent compound.