摘要/Abstract

人脱氧核糖核酸（DNA）拓扑异构酶Ⅱα（topoisomerase Ⅱα，Topo Ⅱα）是重要的抗肿瘤药物靶标之一.为发现高效、低毒的Topo Ⅱα抑制剂，通过对先导化合物6-（3，4-二羟基苯基）萘酚（CS1）进行骨架跃迁，设计合成了21个3-芳基-7-羟基喹啉衍生物.采用DNA松弛实验评价体外Topo Ⅱα抑制活性，结果显示大部分化合物对Topo Ⅱα活性有抑制作用；采用人三阴乳腺癌MDA-MB-231细胞和人宫颈癌HeLa细胞生长抑制实验体外评价抗肿瘤活性，结果表明3-（2，4-二甲氧基苯基）-7-羟基喹啉（4j）对HeLa细胞有明显毒性（IC₅₀=0.8 μmol·L^-1），3-（4-羟基苯基）-7-羟基喹啉（4e）对MDA-MB-231（IC₅₀=1.1 μmol·L^-1）和HeLa（IC₅₀=4.2 μmol·L^-1）细胞均有明显毒性，阳性对照CS1对MDA-MB-231和HeLa细胞的IC₅₀值分别为3.8和2.5 μmol·L^-1.研究结果为设计合成新的喹啉类高效拓扑异构酶Ⅱα抑制剂提供了新思路.
关键词: 拓扑异构酶Ⅱα, 设计合成, 结构优化, 抗肿瘤活性
Human deoxyribonucleic acid (DNA) topoisomerase Ⅱα (Topo Ⅱα) is one of the important therapeutic targets for the treatment of cancers. To further discover Topo Ⅱα inhibitors with high efficiency and low toxicity, twenty-one 3-aryl-7-hydroxyquinolines were designed and synthesized by scaffold hopping of the lead compound 4-(6-hydroxynaph-thalen-2-yl)benzene-1, 2-diol (CS1). These compounds were evaluated for their inhibitory activity against Topo Ⅱα activity in DNA relaxation assays, and evaluated for the antitumor activity in in vitro growth inhibition assays against human triple negative breast cancer MDA-MB-231 cells and human cervical cancer HeLa cells. DNA relaxation assays showed that most compounds have inhibitory activity against Topo Ⅱα. In vitro growth inhibition assays showed that 3-(2, 4-dimethoxyphenyl)-7-hydroxyquinoline (4j) has obvious cytotoxicity against HeLa cells (IC₅₀=0.8 μmol·L^-1), and 3-(4-hydroxyphenyl)-7-hydroxyquinoline (4e) has evident cytotoxicity against both MDA-MB-231 (IC₅₀=1.1 μmol·L^-1) and HeLa cell lines (IC₅₀=4.2 μmol·L^-1). These results provide insight into the development of novel quinoline topoisomerase Ⅱα inhibitors.
Key words: topoisomerase Ⅱα, design and synthesis, structure optimization, antitumor activity


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