Design and synthesis of potent vitamin D receptor antagonists with A-ring modifications:: Remarkable effects of 2α-methyl introduction on antagonistic activity

被引:25
作者
Fujishima, T [1 ]
Kojima, Y
Azumaya, I
Kittaka, A
Takayama, H
机构
[1] Teikyo Univ, Fac Pharmaceut Sci, Sagamiko, Kanagawa 1990195, Japan
[2] Kitasato Univ, Sch Pharmaceut Sci, Tokyo 1088641, Japan
关键词
D O I
10.1016/S0968-0896(03)00371-7
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Novel A-ring analogues of the vitamin D receptor (VDR) antagonist (3a), ZK-159222, and its 24-epimer (3b) were convergently synthesized. Preparation of the CD-ring portions with the side chains of 3a,b, followed by palladium-catalyzed cross-coupling with the A-ring enyne precursors (15a,b), (3S,4S,5R)- and (3S,4S,5S)-bis[(tert-butyldimethylsilyl)oxy]-4-methyloct-1-en-7-yne, afforded the 2alpha-methyl-introduced analogues (4a,b) and their 3-epimers (5a,b). The biological profiles of the hybrid analogues were assessed in terms of affinity for VDR, and antagonistic activity to inhibit HL-60 cell differentiation induced by the natural hormone, 1alpha,25-dihydroxyvitamin D-3. The analogue 4a showed an approximately fivefold higher antagonistic activity compared with 3a. The 2alpha-methyl introduction into 3a increased the receptor affinity, thereby enhancing VDR antagonism. This approach to design potent antagonists based on hybridization of structural motifs in the A-ring and in the side chain may prove to be valuable. (C) 2003 Elsevier Ltd. All rights reserved.
引用
收藏
页码:3621 / 3631
页数:11
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