Conformationally restricted hybrid analogues of the hormone 1 alpha,25-dihydroxyvitamin D-3: Design, synthesis, and biological evaluation

Four new conformationally restricted hybrid analogues of the hormone 1 alph a -25-dihydroxyvitamin D-3 (1,25D3) have been synthesized in a convergent m anner by combining enantiomerically pure C,D-ring ketones (-)-15 and (-)-17 with racemic 1-hydroxymethyl A-ring phosphine oxide (+/-)-18. Parent hybri d analogue 6, which combines the calcemia-inactivating la-hydroxymethyl A-r ing modification with the antiproliferation-activating 20-epi-22-oxa-25-hyd roxydiethyl 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 vi vo. Surprisingly, both conformationally restricted analogues of 6 (8b and 9 b), which incorporate rigidifying units at their 25-hydroxyl side chain ter mini, retained the desirable antiproliferative, transcriptional. and calcem ic activities of the parent compound. (C) 2001 Elsevier Science Ltd. All ri ghts reserved.