Synthesis and biological evaluation of indeno[1, 2-b]indole derivatives as dual topoisomerase Ⅰ & Ⅱ inhibitors: novel multidrug resistant reversal anticancer agents  

茚[1,2-b]并吲哚衍生物的合成、双重抑制拓扑异构酶Ⅰ和Ⅱ及逆转多重耐药等生物活性研究（英文）

作　　者：Dongbo Lu Yu Chen Shan Liu Chao Guo Xia Li Zhongjun Li Xiangbao Meng 卢东渤;陈宇;刘姗;郭超;李霞;李中军;孟祥豹(北京大学医学部药学院天然药物及仿生药物国家重点实验室,化学生物学系,北京100191;山东大学海洋学院,山东威海264209;山东大学药学院,山东济南250012)

机构地区：[1]State Key Laboratory of Natural and Biomimetic Drugs,Department of Chemical Biology,School of Pharmaceutical Sciences,Peking University Health Science Center,Beijing 100191,China [2]School of Ocean,Shandong University,Weihai 264209,China [3]School of Pharmaceutical Sciences,Shandong University,Jinan 250012,China

出　　处：《Journal of Chinese Pharmaceutical Sciences》2019年第11期786-801,共16页中国药学（英文版）

基　　金：The National Natural Science Foundation of China(Grant No.81573272,81273370);Changjiang Scholars and Innovative Research Team in University(Grant No.IRT13028)

摘　　要：A single compound able to inhibit both TopoⅠandⅡmay present the advantage of improving anti-proliferative activity,with reduced toxic side effects,with respect to the combination of two inhibitors.We designed and synthesized 28 compounds of indeno[1,2-b]indole derivatives as a new class of TopoⅠandⅡinhibitor and successfully identified compound 2-3 j,which showed the most potent cell growth inhibition with IC50=0.74μM against HCT-116 cell line.Compound 2-3 j was also evaluated as a potent topoisomeraseⅠandⅡinhibitor and can induce apoptosis in human colon cancer cells.2-3 j showed potency against a small panel of drug sensitive and multidrug resistant(MDR)cell lines,and it reversed the MDR of K562/A02,MCF-7/Adr,and KB/Vcr cells at 0.5μM,with reversal fold values of 3.2,10.1,and 5.8,respectively.2-3 j might inhibit the function of ABCG2 to increase intracellular drug accumulation and enhance the sensitivity of conventional chemotherapeutic agents for MDR cells.2-3 j could be a promising lead for the development of a new class of antitumor drug acting as inhibitors of TopoⅠ&Ⅱand ABCG2.拓扑异构酶Ⅰ和拓扑异构酶Ⅱ双重抑制剂因为具有双靶点,在提高抗增值活性的同时可以降低毒副作用。作者设计并合成了28个茚[1,2-b]并吲哚衍生物类新型拓扑异构酶Ⅰ和Ⅱ抑制剂,并发现化合物2-3j具有最强抗细胞增殖活性,在HCT-116细胞实验中IC50值为0.74μM,且可以诱导人直肠癌细胞凋亡。2-3j不仅对药物敏感细胞系有活性,对于多重抗药(MDR)细胞系K562/A02,MCF-7/Adr和KB/Vcr细胞均有逆转抗药性作用,逆转抗药性倍数变化分别为3.2,10.1和5.8。2-3j的作用机理可能是通过抑制ABCG2活性,提高药物细胞内浓度,从而增强MDR细胞对传统化疗药物的敏感度。2-3j可以作为潜在的新型拓扑异构酶Ⅰ&Ⅱ和ABCG2抑制剂先导化合物进行进一步开发和研究。

关 键 词：Indeno[1 2-b]indole ANTI-CANCER TopoisomerseⅠ&Ⅱinhibitor Reverse multi-drug resistance 

分 类 号：R914[医药卫生—药物化学]