Synthesis and biological evaluation of benzo[a]phenazine derivatives as a dual inhibitor of topoisomerase I and II
Synthesis and biological evaluation of benzo[a]phenazine derivatives as a dual inhibitor of topoisomerase I and II
复制标题
拓扑异构酶 I 和 II 双重抑制剂苯并[a]吩嗪衍生物的合成及生物学评价
DOI：
10.1039/c3ob40325d
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发表时间：
2013-01-01
影响因子：
3.2
通讯作者：
Huang, Zhi-Shu
中科院分区：
文献类型：
--
作者：
Zhuo, Shi-Tian;Li, Chun-Yan;Huang, Zhi-Shu
拓扑异构酶（Topo I和Topo II）在DNA复制、修复和转录中起着非常重要的作用，是一类很有前途的抗肿瘤靶点。本研究设计、合成了一系列C-5侧链为烷基胺的苯并[a]非那嗪衍生物，并对其生物活性进行了评价。大部分衍生物对4种癌细胞HeLa、A549、MCF-7和HL-60均表现出良好的抗增殖活性，IC50值范围在1 ~ 10 μ M之间。拓扑异构酶介导的DNA松弛实验结果表明，衍生物可以有效抑制Topo I和Topo II的活性，构效关系研究表明引入烷基胺侧链的重要性。进一步的机制研究表明，化合物可以稳定Topo I- dna切割复合物，抑制Topo II的atp酶活性，表明它们是一类罕见的双重拓扑异构酶抑制剂，可以作为Topo I毒素和Topo II催化抑制剂。流式细胞分析和caspase-3/7活化实验表明，该类化合物可诱导HL-60细胞凋亡。
Topoisomerases (Topo I and Topo II) are very important players in DNA replication, repair, and transcription, and are a promising class of antitumor target. In present study, a series of benzo[a]phenazine derivatives with alkylamino side chains at C-5 were designed, synthesized, and their biological activities were evaluated. Most of derivatives showed good antiproliferative activity with a range of IC50 values of 1-10 mu M on the four cancer cell lines HeLa, A549, MCF-7, and HL-60. Topoisomerase-mediated DNA relaxation assay results showed that derivatives could effectively inhibit the activity of both Topo I and Topo II, and the structure-activity relationship studies indicated the importance of introducing an alkylamino side chain. Further mechanism studies revealed that the compounds could stabilize the Topo I-DNA cleavage complexes and inhibit the ATPase activity of hTopo II, indicating that they are a rare class of dual topoisomerase inhibitors by acting as Topo I poisons and Topo II catalytic inhibitors. Moreover, flow cytometric analysis and caspase-3/7 activation assay showed that this class of compounds could induce apoptosis of HL-60 cells.