36 スピロ環構造を有する新規2位修飾活性型ビタミンD誘導体の合成,及びビタミンD受容体への結合様式解析(口頭発表の部)

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All possible stereoisomers of 2,2-dimethyl-1,25-dihydroxyvitamin D_3 (4a-d) were designed and convergently synthesized, in view of the important effects of the 2α-methyl substitution on the A-ring of the natural hormone, 1α,25-dihydroxyvitamin D_3 (1). Nine-step conversion of methyl hydroxypivalate (8) provided the desired A-ring enyne synthon (15a,b) in good overall yield. Palladium-catalyzed cross-coupling reaction of the A-ring synthon (15a,b) with the CD-ring portion, followed by deprotection, gave the 2,2-dimethyl analogues (4a-d). The stereochemistry of the C1 and C3 positions was determined by the modified Mosher's method using their bis-MTPA esters. Applying the above procedures, we also synthesized 2,2-ethano-, 2,2-propano- and 2,2-butano-1,25-dihydroxyvitamin D_3 (5-7), as novel spiro-ring analogues having cyclopropane, cyclobutane and cyclopentane fused at the C2 position, respectively. Biological potencies of the synthesized compounds were assessed in terms of vitamin D receptor (VDR) binding affinity, as well as the HL-60 cell differentiation-inducing activity. The 2,2-ethano analogue (5a) showed a comparable activity to the natural hormone (1), while the 2,2-dimethyl analogue (4a) proved to be a weak binder to VDR. These features were explained, in part, by the docking studies based on the X-ray crystal structure of VDR complexed with 1.
天然有機化合物討論会の論文
2003-09-01