Enantiopure fluorine-containing taxoids: potent anticancer agents and versatile probes for biomedical problems

被引:54
作者
Ojima, I [1 ]
Inoue, T [1 ]
Chakravarty, S [1 ]
机构
[1] SUNY Stony Brook, Dept Chem, Stony Brook, NY 11794 USA
基金
美国国家卫生研究院;
关键词
taxol; taxotere; fluorine-containing taxoid; SAR; metabolism; fluorine probe approach;
D O I
10.1016/S0022-1139(99)00058-5
中图分类号
O61 [无机化学];
学科分类号
070301 ; 081704 ;
摘要
Fluorine-containing paclitaxel and docetaxel analogs are reported that are obtained through the coupling of enantiopure (3R,4S)-1-acyl-beta -lactams with various baccatins. Some taxoids hearing the trifluoromethyl or difluoromethyl groups at the C-3' position possessed three orders of magnitude greater potency than either paclitaxel or doxorubicin against both sensitive and drug-resistant human breast cancer cell lines. The incorporation of fluorine in taxoids as a probe has been successfully exploited for the study of their metabolism and structure. Fluorine-containing taxoids are shown to block the metabolic pathways associated with the cytochrome P-450 class of enzymes. Structural studies using F-19 and H-1 NMR techniques on fluorine-containing taxoids in combination with molecular modeling have provided new insights into the biologically relevant conformations of taxoids in solution as well as in the microtubule-bound state. (C) 1999 Elsevier Science S.A. All rights reserved.
引用
收藏
页码:3 / 10
页数:8
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