Design, synthesis and biological evaluation of novel 7-alkylamino substituted benzo[a]phenazin derivatives as dual topoisomerase I/II inhibitors.
Design, synthesis and biological evaluation of novel 7-alkylamino substituted benzo[a]phenazin derivatives as dual topoisomerase I/II inhibitors.
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DOI：
10.1016/j.ejmech.2015.01.024
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发表时间：
2015-03
影响因子：
6.7
通讯作者：
Bing Yao;Yan-wen Mai;Shuo-Bin Chen;Hua-Ting Xie;Pei-fen Yao;Tian-Miao Ou;Jia-Heng Tan;Honggen Wang;Ding Li;Shi-Liang Huang;L. Gu;Zhishu Huang
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文献类型：
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作者：
Bing Yao;Yan-wen Mai;Shuo-Bin Chen;Hua-Ting Xie;Pei-fen Yao;Tian-Miao Ou;Jia-Heng Tan;Honggen Wang;Ding Li;Shi-Liang Huang;L. Gu;Zhishu Huang
设计、合成了一系列带有烷基胺侧链的苯并[A]吩那嗪衍生物，并对其拓扑异构酶抑制活性和对四种人类癌细胞（HL-60、K-562、HeLa和A549）的细胞毒性进行了评价。这些化合物被发现是拓扑异构酶（Topo） I和Topo II的双重抑制剂，并表现出优异的抗增殖活性，特别是对具有亚微摩尔ic50值的HL-60细胞。进一步的机制研究表明，这类化合物通过稳定Topo I- dna切割复合物和抑制Topo II的atp酶活性来发挥Topo I毒素的作用。分子对接研究揭示了这些化合物与Topo I和Topo II的结合模式。
A novel series of benzo[a]phenazin derivatives bearing alkylamino side chains were designed, synthesized and evaluated for their topoisomerases inhibitory activity as well as cytotoxicity against four human cancer cell lines (HL-60, K-562, HeLa, and A549). These compounds were found to be dual inhibitors of topoisomerase (Topo) I and Topo II, and exhibited excellent antiproliferative activity, in particular against HL-60 cells with submicromolar IC50values. Further mechanistic studies showed that this class of compounds acted as Topo I poisons by stabilizing the Topo I-DNA cleavage complexes and Topo II catalytic inhibitors by inhibiting the ATPase activity ofhTopo II. Molecular docking studies revealed the binding modes of these compounds for Topo I and Topo II.