Syntheses and antiproliferative activities of 7-azarebeccamycin analogues bearing one 7-azaindole moiety
Syntheses and antiproliferative activities of 7-azarebeccamycin analogues bearing one 7-azaindole moiety
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DOI：
10.1021/jm0210055
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发表时间：
2003-02-13
影响因子：
7.3
通讯作者：
Prudhomme, M
中科院分区：
文献类型：
--
作者：
Marminon, C;Pierré, A;Prudhomme, M
合成了含有一个氮杂环的雷贝卡霉素类似物，在酰亚胺氮上有甲基和不带甲基，糖基部分偶联到吲哚氮或氮杂多尔氮上。在吲哚单元上引入了溴取代基或硝基取代基，以增加溶解度并诱导与目标大分子更强的相互作用。研究了其对DNA结合和拓扑异构酶I的抑制作用，以及对9种肿瘤细胞株的抗增殖活性。此外，还检测了化合物对L1210白血病细胞周期的影响。研究发现，九氮类似物对所有细胞株均有细胞毒作用，而氮杂类似物对某些细胞系有选择性作用。它们对SK-N-MC神经母细胞瘤、A431表皮样癌和NCI-H69小细胞肺癌细胞的增殖均有较强的抑制作用，而对卵巢癌、HT29结肠癌和A549非小细胞肺癌细胞几乎没有细胞毒作用。无论它们的细胞毒性特征如何，所有化合物都会引起相似的细胞周期效应，在L1210白血病细胞中观察到明显的G2+M期阻滞。这些数据表明，氮杂类似物的分子作用机制与瑞贝卡霉素不同。
Rebeccamycin analogues containing one azaindole unit, with and without a methyl group on the imide nitrogen and with the sugar moiety coupled either to the indole nitrogen or to the azaindole nitrogen were synthesized. To increase the solubility and induce stronger interactions with the target macromolecules, a bromo or nitro substitutent was introduced on the indole unit. The DNA binding and topoisomerase I inhibition properties were investigated together with the antiproliferative activities toward nine tumor cell lines. In addition, the effect of the compounds on the cell cycle of L1210 leukemia cells was examined. The nonaza analogues were found to be cytotoxic against all cell lines of the panel whereas the aza-analogues showed a selective action toward certain cell lines. They strongly inhibited the proliferation of SK-N-MC neuroblastoma, A431 epidermoid carcinoma and NCI-H69 small cell lung carcinoma cells, but showed little or no cytotoxic effect against IGROV ovary carcinoma, HT29 colon carcinoma, and A549 non small cell lung carcinoma cells. Whatever their cytotoxicity profile, all compounds induce similar cell cycle effects, with a marked G2+M block observed with L1210 leukemia cells. The data suggest that the molecular mechanism of action of the aza-analogue derivatives is different from that of rebeccamycin.