(E)-N-(4-苯乙烯基)丙烯酰胺类DNA拓扑异构酶Ⅱα抑制剂的合成及抗肿瘤活性研究  

Synthesis of(E)-N-(4-Styrene)Acrylamides for DNA TopoisomeraseⅡαInhibitors and Antitumor Agents

作　　者：尹丽君 李超群 吴晓霞 徐广森 李志颖 沈月毛[1] Yin Lijun;Li Chaoqun;Wu Xiaoxia;Xu Guangsen;Li Zhiying;Shen Yuemao(Key Laboratory of Chemical Biology,Ministry of Education,School of Pharmaceutical Sciences,Shandong University,Jinan 250012)

机构地区：[1]山东大学药学院,天然产物化学教育部重点实验室,济南250012

出　　处：《有机化学》2022年第1期293-301,共9页Chinese Journal of Organic Chemistry

基　　金：国家重点基础研究发展计划(973计划,No.2010CB833802);国家自然科学基金(Nos.81273384,90913024,91313303);长江学者和创新团队发展计划(IRT_17R68);国家杰出青年科学基金(No.30325044)资助项目。

摘　　要：人DNA拓扑异构酶Ⅱα(topoisomeraseⅡα,TopoⅡα)是重要的抗肿瘤药物靶标之一.为发现新的高效、低毒TopoⅡα抑制剂,本研究通过对先导化合物CL-2进行骨架跃迁,设计合成了18个(E)-N-(4-苯乙烯基)丙烯酰胺衍生物(A1~A9,B1~B9).18个化合物对人三阴性乳腺癌MDA-MB-231细胞和人急性骨髓性白血病KG1细胞生长的抑制实验结果表明,(E)-N-(4-((E)-3,5-二羟基苯乙烯基)苯基)-3-(邻-甲苯基)丙烯酰胺(B1)和(E)-N-(4-((E)-3,5-二羟基苯乙烯基)苯基)-3-(4-硝基苯基)丙烯酰胺(B9)抑制KG1细胞生长的IC_(50)分别为0.43和0.5μmol/L;(E)-N-(4-((E)-3,5-二羟基苯乙烯基)苯基)-3-(2-羟基苯基)丙烯酰胺(B4)对MDA-MB-231细胞的生长抑制作用(IC_(50)=0.82μmol/L)超过阳性对照VP16(IC_(50)=6.62μmol/L).(E)-N-(4-((E)-3,5-二甲氧基苯乙烯基)苯基)-3-(邻-甲苯基)丙烯酰胺(A1)、B1、(E)-N-(4-((E)-3,5-二甲氧基苯乙烯基)苯基)-3-(2-甲氧苯基)丙烯酰胺(A4)、B4、(E)-N-(4-((E)-3,5-二甲氧基苯乙烯基)苯基)-3-(噻吩-3-基)丙烯酰胺(A9)和B9体外抑制TopoⅡα介导的DNA松弛作用.研究结果为发现新骨架TopoⅡα抑制剂提供了新方向.Human DNA topoisomeraseⅡα(TopoⅡα)is one of the important targets of antitumor drugs.In this study,eighteen(E)-N-(4-styrene)acrylamide derivatives(A1~A9,B1~B9)were designed and synthesized through skeleton hopping of the lead compound CL-2 for the discovery of new high-efficient and low-toxic TopoⅡαinhibitors.In vitro growth inhibition experiments of human triple negative breast cancer MDA-MB-231 cells and human acute myeloid leukemia KG1 cells were carried out for these eighteen compounds.Amongst,(E)-N-(4-((E)-3,5-dihydroxystyryl)phenyl)-3-(o-tolyl)acrylamide(B1)and(E)-N-(4-((E)-3,5-dihydroxystyryl)phenyl)-3-(4-nitrophenyl)acrylamide(B9)showed evident cytotoxicity against the KG1 cells with the IC_(50)values of 0.43 and 0.5μmol/L,respectively.(E)-N-(4-((E)-3,5-dihydroxyphenyl)phenyl)-3-(2-hydroxyphenyl)acrylamide(B4)showed stronger growth inhibitory effect(IC_(50)=0.82μmol/L)against the MDA-MB-231 cells than that of the positive control VP16(IC_(50)=6.62μmol/L).(E)-N-(4-((E)-3,5-Dimethoxystyryl)phenyl)-3-(o-tolyl)-acrylamide(A1)、B1、(E)-N-(4-((E)-3,5-dimethoxystyryl)phenyl)-3-(2-methoxyphenyl)acrylamide(A4)、B4、(E)-N-(4-((E)-3,5-dimethoxystyryl)phenyl)-3-(thiophen-3-yl)acrylamide(A9)and B9 inhibited TopoⅡα-mediated DNA relaxation in vitro.These results provide a new direction for the discovery of new skeleton TopoⅡαinhibitors.

关 键 词：拓扑异构酶Ⅱα 设计合成 结构优化 抗肿瘤活性 

分 类 号：TQ460.1[化学工程—制药化工]