New water-soluble duocarmycin derivatives:: Synthesis and antitumor activity of A-ring pyrrole compounds bearing β-heteroarylacryloyl groups

被引:31
作者
Amishiro, N [1 ]
Nagamura, S [1 ]
Kobayashi, E [1 ]
Gomi, K [1 ]
Saito, H [1 ]
机构
[1] Kyowa Hakko Kogyo Co Ltd, Pharmaceut Res Inst, Shizuoka 4110943, Japan
关键词
D O I
10.1021/jm980559y
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A series of A-ring pyrrole compounds of duocarmycin bearing 4'-methoxy-beta-heteroarylacryloyl groups were synthesized and evaluated for in vitro anticellular activity against HeLa S-3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. Most of the Li 4'-methoxy-beta-heteroarylacrylates displayed in vitro anticellular activity equivalent to that of 4'-methoxycinnamates, Among the 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxy-beta-heteroarylacrylates, compound 15b having a (4-methoxy-3,5-pyrimidinyl)acryloyl as segment-B (Seg-B) showed remarkably potent in vivo antitumor activity and low peripheral blood toxicity compared with the A-ring pyrrole derivatives having the trimethoxyindole skeleton in Seg-B, which were equal to 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxycinnamates. Moreover, these 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxy-beta-heteroarylacrylates had high aqueous solubility.
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页码:669 / 676
页数:8
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