有机化学 ›› 2018, Vol. 38 ›› Issue (11): 3039-3047.DOI: 10.6023/cjoc201805035 上一篇    下一篇

所属专题: 有机小分子-金属协同催化

研究论文

拟天然联三苯类拓扑异构酶IIα抑制剂的设计合成

关梦佳, 邱进, 鲁春华, 赵保兵, 沈月毛   

  1. 山东大学药学院 天然产物化学生物学教育部重点实验室 济南 250012
  • 收稿日期:2018-05-16 修回日期:2018-06-14 出版日期:2018-11-25 发布日期:2018-07-16
  • 通讯作者: 赵保兵 E-mail:baobingzh@gmail.com
  • 基金资助:

    国家基础研究计划(937项目,No.2010CB883802)、国家自然科学基金(Nos.81373304,81273384)、教育部创新团队(No.IRT_17R68)和国家杰出青年科学基金(No.30325044)资助项目.

Design and Synthesis of Natural Product-Like Terphenyl as Potent Topoisomerase IIα Inhibitors

Guan Mengjia, Qiu Jin, Lu Chunhua, Zhao Baobing, Shen Yuemao   

  1. Key Laboratory of Chemical Biology(Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250012
  • Received:2018-05-16 Revised:2018-06-14 Online:2018-11-25 Published:2018-07-16
  • Supported by:

    Project supported by the National Basic Research Program (973 Program, No. 2010CB833802), the National Natural Science Foundation of China (Nos. 81373304, 81273384), the program for Innovative Research Team in University of Ministry of Education of China (No. IRT_17R68) and the National Science Found for Distinguished Young Scholars of China (No. 30325044).

设计合成了系列新的拟天然联三苯类衍生物,并对其生物活性进行了分析.其中4-氨基-(1,1':4,1'-三联苯)-3-二醇(17)具有最强的MDA-MB-435细胞增殖抑制活性,IC50为(0.20±1.12)μmol/L,显著优于我们之前报道的同类化合物X1X2.DNA松弛实验结果表明,化合物17具有较强的DNA拓扑异构酶Ⅱα的抑制活性,但是对DNA拓扑异构酶I活性无明显抑制作用.分子模拟对接分析结果进一步验证,C环上的氮取代基对化合物17选择性抑制DNA拓扑异构酶Ⅱα活性有重要作用,为设计合成新的联三苯类高效拓扑异构酶Ⅱα抑制剂提供了新思路.

关键词: 拓扑异构酶, 联三苯, 抑制剂, 抗肿瘤

A series of natural product-like terphenyls were synthesized, and their biological activities were evaluated. 4"-Amino-[1,1':4',1"-terphenyl]-3,4-diol (17) has the most potent cytotoxic activity against the MDA-MB-435 cell line, and the IC50 value is (0.20±1.12) μmol/L, which is more potent than compounds X1 and X2 obtained in our previous studies. DNA relaxation test showed that compound 17 had a strong inhibitory effect on topoisomerase Ⅱα (TOP2α), but not on topoisomerase I (TOP1), which was consistent with the docking analysis results. Our studies demonstrate that N contained substitutes on ring C are important for producing terphenyls with more efficacious activity against TOP2α, which provide insight into the development of novel terphenyl topoisomerase Ⅱα inhibitors.

Key words: topoisomerase, terphenyls, inhibitor, antitumor