Design and synthesis of potent antitumor 5,4'-diaminoflavone derivatives based on metabolic considerations

被引:67
作者
Akama, T [1 ]
Ishida, H [1 ]
Shida, Y [1 ]
Kimura, U [1 ]
Gomi, K [1 ]
Saito, H [1 ]
Fuse, E [1 ]
Kobayashi, S [1 ]
Yoda, N [1 ]
Kasai, M [1 ]
机构
[1] KYOWA HAKKO KOGYO CO LTD,PHARMACEUT RES LABS,NAGAIZUMI,SHIZUOKA 411,JAPAN
关键词
D O I
10.1021/jm9700326
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Recently, we reported that 5,4'-diaminoflavone (1) exhibits potent and specific growth-inhibitory activity against the estrogen receptor (ER)-positive human breast cancer cell line MCF-7. However, when compound 1 was incubated with S-9 mix, its metabolites were observed. Moreover, addition of S-9 mix to the medium caused the drastic decrease in activity of compound 1. Since the 6-, 8-, and 3'-positions were considered to be metabolized oxidatively in vivo from MO calculations, a series of 5,4'-diaminoflavone derivatives substituted at such putative metabolic positions with various functional groups were synthesized aiming at the metabolically stable derivatives. Among them, 5,4'-diaminoflavone-6,8,3'-trifluoroflavone (14d) exhibited strong growth-inhibitory activity against MCF-7 cells even in the presence of S-9 mix. Moreover, orally administered compound 14d completely suppressed the growth of MCF-7 inoculated into nude mice, and the effect was more potent than that of compound 1. In addition to ER-positive breast cancer cells, compound 14d exhibited growth-inhibitory activity against a panel of human cancer cell lines including a part of ER-negative breast, endometrial, ovarian, and liver cancers. From these results, fluorine introduction to the putative metabolic positions of compound 1 was elucidated to be effective in the enhancement of the in vivo antitumor activity, probably due to the block of the metabolic deactivation.
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页码:1894 / 1900
页数:7
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