Highly potent cell differentiation-inducing analogues of 1α,25-dihydroxyvitamin D3:: Synthesis and biological activity of 2-methyl-1,25-dihydroxyvitamin D3 with side-chain modifications

Eight 2-methyl substituted analogues of 20-epi-22R-methyl-1 alpha ,25-dihydroxyvitamin D-3 (5) and 20-epi-24,26,27-trihomo-22-oxa-1 alpha ,25-dihydroxyvitamin D-3 (6. KH-1060) were convergently synthesized. Preparation of the CD-ring portions with modified side chains of 5 and 6, followed by palladium-catalyzed cross-coupling with the A-ring enyne synthons (20a-d), (3S,4S,5R)-, (3S,4R,5R)-, (3S,4S,5S)- and (3R,4R,5S)-3.5-bis[(tert-butyldimethylsilyl)oxy]4-methyloct-1-en-7-yne, afforded two sets of four A-ring stereoisomers of 20-epi-2,22-dimethyl-1,25-dihydroxyvitamin D-3 (7a-d) and 20-epi-24,26,27-trihomo-2-methyl-22-oxa-1,25d-dihydroxyvitamin D-3 (8a-d). The biological profiles of the hybrid analogues were assessed in terms of affinity for vitamin D receptor (VDR) and HL-60 cell differentiation-inducing activity in comparison with the: natural hormone. The combined modifications of the A-ring at the 2-position and the side chain yielded analogues with high, potency. (C) 2001 Elsevier Science Ltd. All rights reserved.