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

doi:10.5246/jcps.2019.11.075

Abstract

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

CLC Number:

R914

Supporting:

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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