Novel benzopyridothiadiazepines as potential active antitumor agents
Novel benzopyridothiadiazepines as potential active antitumor agents
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DOI：
10.1021/jm0503897
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发表时间：
2005-11-17
影响因子：
7.3
通讯作者：
Berthelot, P
中科院分区：
文献类型：
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作者：
Lebegue, N;Gallet, S;Berthelot, P
报道了可作为E-7010的限制类似物的新型硫二氮杂衍生物的合成。评估了这些分子对小鼠L1210白血病细胞系的抗增殖活性。对L1210细胞进行的流式细胞仪检测显示，细胞在细胞周期的G2/M期积累，并有相当比例的四倍体细胞(8NDNA含量)。化合物2b、4b、4e、4g和4i具有亚微摩尔细胞毒性。其中化合物2b和4b对微管蛋白聚合有较强的抑制作用，其IC50分别为3.8和2.4mM，而对脱氧鬼臼毒素的IC50为2.4mM。苯并吡啶并硫二氮杂环上的4-甲氧基苯乙基取代是其抗增殖活性所必需的。化合物2b和4b的体外活性使苯并吡喃并硫二氮杂二氧化物成为一类有希望的新型微管蛋白结合剂，值得进一步在体内进行评价。
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.