Antitumor and Topoisomerase IIα Inhibitory Activities of 3-Aryl-7-hydroxyquinolines
a 山东大学药学院 天然产物化学教育部重点实验室 济南 250012) ( b 山东大学附属省立医院药剂科 济南 250021) 摘要 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(IC 50 =0.8 μmol•L -1 ), 3-(4-羟基苯基)-7-羟基喹啉(4e)对 MDA-MB-231 Abstract Human deoxyribonucleic acid (DNA) topoisomerase
... NA) 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-hydroxynaphthalen-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)-7hydroxyquinoline (4j) has obvious cytotoxicity against HeLa cells (IC 50 =0.8 μmol•L -1 ), and 3-(4-hydroxyphenyl)-7hydroxyquinoline (4e) has evident cytotoxicity against both MDA-MB-231 (IC 50 =1.1 μmol•L -1 ) and HeLa cell lines (IC 50 = 4.2 μmol•L -1 ). These results provide insight into the development of novel quinoline topoisomerase IIα inhibitors.