- 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
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Eight 2-methyl substituted analogues of 20-epi-22R-methyl-1α,25-dihydroxyvitamin D3 (5) and 20-epi-24,26,27-trihomo-22-oxa-1α,25-dihydroxyvitamin D3 (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 D3 (7a-d) and 20-epi-24,26,27-trihomo-2-methyl-22-oxa-1,25-dihydroxyvitamin D3 (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.
- Fujishima, Toshie,Zhaopeng, Liu,Konno, Katsuhiro,Nakagawa, Kimie,Okano, Toshio,Yamaguchi, Kentaro,Takayama, Hiroaki
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p. 525 - 535
(2007/10/03)
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