Conformationally Restricted Hybrid Analogues of the Hormone 1α,25-Dihydroxyvitamin D 3: Design, Synthesis, and Biological Evaluation

Abstract

Four new conformationally restricted hybrid analogues of the hormone 1α-25-dihydroxyvitamin D 3 (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 incorporate rigidifying units at their 25-hydroxyl side chain termini, retained the desirable antiproliferative, transcriptional, and calcemic activities of the parent compound.