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

doi:10.5246/jcps.2019.11.075

中国药学(英文版) ›› 2019, Vol. 28 ›› Issue (11): 786-801.DOI: 10.5246/jcps.2019.11.075

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

卢东渤¹, 陈宇¹, 刘姗¹, 郭超², 李霞^2,3*, 李中军¹, 孟祥豹^1*

1. 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
2. 山东大学海洋学院, 山东威海 264209
3. 山东大学药学院, 山东济南 250012

收稿日期:2019-05-27 修回日期:2019-07-15 出版日期:2019-12-01 发布日期:2019-08-23
通讯作者: Tel.: +86-10-82801714, E-mail: xbmeng@bjmu.edu.cn; xiali@sdu.edu.cn
基金资助:
The National Natural Science Foundation of China (Grant No. 81573272, 81273370), Changjiang Scholars and Innovative Research Team in University (Grant No. IRT13028).

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

Dongbo Lu¹, Yu Chen¹, Shan Liu¹, Chao Guo², Xia Li^2,3*, Zhongjun Li¹, Xiangbao Meng^1*

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

Received:2019-05-27 Revised:2019-07-15 Online:2019-12-01 Published:2019-08-23
Contact: Tel.: +86-10-82801714, E-mail: xbmeng@bjmu.edu.cn; xiali@sdu.edu.cn
Supported by:
The National Natural Science Foundation of China (Grant No. 81573272, 81273370), Changjiang Scholars and Innovative Research Team in University (Grant No. IRT13028).

摘要/Abstract

摘要：

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0.74 μM, 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: 茚[1, 2-b]并吲哚, 抗肿瘤, 拓扑异构酶I和II抑制剂, 逆转多重耐药

Abstract:

A single compound able to inhibit both Topo I and II may 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 Topo I and II inhibitor and successfully identified compound 2-3j, which showed the most potent cell growth inhibition with IC₅₀=0.74 μM against HCT-116 cell line. Compound 2-3j was also evaluated as a potent topoisomerase I and II inhibitor and can induce apoptosis in human colon cancer cells. 2-3j 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 0.5 μM, with reversal fold values of 3.2, 10.1, and 5.8, respectively. 2-3j might inhibit the function of ABCG2 to increase intracellular drug accumulation and enhance the sensitivity of conventional chemotherapeutic agents for MDR cells. 2-3j could be a promising lead for the development of a new class of antitumor drug acting as inhibitors of Topo I & II and ABCG2.

Key words: Indeno[1, 2-b]indole, Anti-cancer, Topoisomerse I &, II inhibitor, Reverse multi-drug resistance

中图分类号:

R914

Supporting:

卢东渤, 陈宇, 刘姗, 郭超, 李霞, 李中军, 孟祥豹. 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[J]. 中国药学(英文版), 2019, 28(11): 786-801.

Dongbo Lu, Yu Chen, Shan Liu, Chao Guo, Xia Li, Zhongjun Li, Xiangbao Meng. Synthesis and biological evaluation of indeno[1, 2-b]indole derivatives as dual topoisomerase I & II inhibitors: novel multidrug resistant reversal anticancer agents[J]. Journal of Chinese Pharmaceutical Sciences, 2019, 28(11): 786-801.

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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

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

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