Novel benzopyridothiadiazepines as potential active antitumor agents

被引:83
作者
Lebegue, N
Gallet, S
Flouquet, N
Carato, P
Pfeiffer, B
Renard, P
Léonce, S
Pierré, A
Chavatte, P
Berthelot, P
机构
[1] Fac Sci Pharmaceut & Biol Lille, EA1043, Chim Therapeut Lab, F-59006 Lille, France
[2] Inst Rech Servier, Div Rech Cancerol, F-78290 Croissy Sur Seine, France
关键词
D O I
10.1021/jm0503897
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The synthesis of novel thiadiazepine derivatives, that could be considered as constraint analogues of E-7010, are reported. These molecules were evaluated for their antiproliferative activity toward the murine L1210 leukemia cell line. Flow cytometric studies performed on L1210 cells with the most cytotoxic compounds showed an accumulation of the cells in the G2/M phases of the cell cycle with a significant percentage of tetraploid cells (8N DNA content). Submicromolar cytotoxicities were observed with compounds 2b, 4b, 4e, 4g, and 4i. Two of them, compounds 2b and 4b, were found to be potent inhibitors of tubulin polymerization with IC50 of respectively 3.8 and 2.4 mu M compared to 2.4 mu M for desoxypodophyllotoxin. A 4-methoxyphenylethyl substitution on the pyridinyl nitrogen of the benzopyridothiadiazepine was found to be essential for the antiproliferative activity. The in vitro activities of compounds 2b and 4b make benzopyridothiadiazepine dioxides a promising new class of tubulin binders which warrant further in vivo evaluation.
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收藏
页码:7363 / 7373
页数:11
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