Four new conformationally restricted hybrid analogues of the hormone 1 alpha-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 1 beta-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.