Syntheses and biological activities of rebeccamycin analogues with uncommon sugars
Syntheses and biological activities of rebeccamycin analogues with uncommon sugars
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DOI：
10.1021/jm0493764
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发表时间：
2005-04-07
影响因子：
7.3
通讯作者：
Wang, PG
中科院分区：
文献类型：
--
作者：
Zhang, GS;Shen, J;Wang, PG
已合成了含有不常见糖和酰亚胺氮上的取代基的斯卡霉素类似物。在结肠癌和白血病细胞中测试了它们的细胞毒性。在Hela细胞中使用拓扑异构酶生物测定的体内复合物检查它们靶向拓扑异构酶I的能力。与苷元1相比，具有不同糖基的修饰化合物显示出更强的细胞毒性和拓扑异构酶I靶向能力。此外，含有各种不常见糖的瑞贝卡霉素类似物显示出不同的细胞毒性和拓扑异构酶I靶向活性。含2-脱氧葡萄糖的化合物（8和9）>含2，6-脱氧葡萄糖的化合物（5和6）>含2，3，6-脱氧葡萄糖的化合物（10）。此外，化合物的抗癌活性与其靶向内源性拓扑异构酶I的能力相关。这些结果表明，糖部分，特别是糖的2-OH和6-OH基团，而不是吲哚并咔唑环上酰亚胺结构的修饰，是其活性的关键因素。
Rebeccamycin analogues containing uncommon sugars and substitutions on the imide nitrogen have been synthesized. Their cytotoxicities were tested in colon cancer and leukemia cells. Their ability to target topoisomerase I was examined using the in vivo complex of the topoisomerase bioassay in Hela cells. Compared with aglycon 1, the modified compounds with various sugar moieties showed more potent cytotoxicities and topo I targeting ability. In addition, the rebeccamycin analogues with various uncommon sugars showed distinct cytotoxicities and topo I targeting activities. The activity of compounds with 2-deoxyglucose (8 and 9) > compounds with 2,6-deoxyglucose (5 and 6) > compounds with 2,3,6-deoxyglucose (10). Furthermore, the anticancer activity of compounds correlated with their ability to target endogenous topo I. These results suggest that the sugar moiety, especially the 2-OH and 6-OH group of the sugar, rather than the modifications in imide structure on the indolocarbazole ring, is a key element for its activity.