Highly potent cell differentiation-inducing analogues of 1alpha,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-1alpha,25-dihydroxyvitamin D3 (5) and 20-epi-24,26,27-trihomo-22-oxa-1alpha,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
T
T
Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa, Japan.
Zhaopeng
L
L
Konno
K
K
Nakagawa
K
K
Okano
T
T
Yamaguchi
K
K
Takayama
H
H
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001667:Binding, Competitive; D002117:Calcitriol / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D018360:Crystallography, X-Ray; D018922:HL-60 Cells; D006801:Humans; D015394:Molecular Structure; D011485:Protein Binding; D018167:Receptors, Calcitriol / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014807:Vitamin D / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology
C116441:2-methyl-1,25-dihydroxyvitamin D3; D000970:Antineoplastic Agents; D018167:Receptors, Calcitriol; D014807:Vitamin D; D002117:Calcitriol