Steroids p. 277 - 285 (2001)
Update date:2022-08-05
Topics:
Takayama, Hiroaki
Konno, Katsuhiro
Fujishima, Toshie
Maki, Shojiro
Liu, Zhaopeng
Miura, Daishiro
Chokki, Manabu
Ishizuka, Seiichi
Smith, Connie
DeLuca, Hector F.
Nakagawa, Kimie
Kurobe, Mayuko
Okano, Toshio
All possible A-ring diastereomers of 2-methyl-1α,25-dihydroxyvitamin D3 (2) and 20-epi-2-methyl-1α,25-dihydroxyvitamin D3 (3) were synthesized by palladium-catalyzed coupling reaction of A-ring 'enyne' synthons with CD-ring portions. The A-ring synthons were rationally synthesized via a novel and practical route, starting with methyl (R)-(+)- and (S)-(-)-3-hydroxy-2-methyl-propionate, in good yields. X-ray crystallographic analysis of 2α-methyl-1α,25-dihydroxyvitamin D3 (2b) and conformational analysis of the A-ring of 2α-methyl-(2b) and 2β-methyl-1α,25-dihydroxyvitamin D3 (2f) were carried out, and the results are described. All A-ring diastereomers (2 and 3), thus synthesized, were biologically evaluated both in vitro and in vivo. The biologic potency was highly dependent on the stereochemistry of the A-ring substituents. In particular, 2b showed 4-fold higher vitamin D receptor [VDR] binding activity than the natural hormone, and its 20-epimer (3b) exhibited exceptionally high activity, 12-fold more potent in VDR binding, 7-fold in calcium mobilization, and 590-fold in induction of human promyelocytic leukemia (HL-60) cell differentiation as compared with the natural hormone. Further, the 20-epi-2β-Me-1β, 3α(OH)2 isomer (3g) had significant biologic potencies compared to the natural hormone despite having 1β-OH configuration. The transcriptional activities on human osteocalcin gene promoter, including VDRE in transfected mammalian cells, were also evaluated. Finally, there was a clear contrast between the effects of the 2-methyl group on the HL-60 cell differentiation- and apoptosis-inducing activities of 2 and 3. Copyright
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(2001)