Synthesis and biological evaluation of novel pyrazoline derivatives containing indole skeleton as anti-cancer agents targeting topoisomerase II

Eur J Med Chem. 2020 Aug 15:200:112459. doi: 10.1016/j.ejmech.2020.112459.

Yali Song ¹, Siran Feng ², Jiajia Feng ², Jinjiao Dong ², Kan Yang ², Zhenming Liu ³, Xiaoqiang Qiao ⁴

Affiliations

1 Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, Hebei, 071002, China. Electronic address: yalisong@hbu.edu.cn.
2 Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, Hebei, 071002, China.
3 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
4 Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding, Hebei, 071002, China; Key Laboratory of Medicinal Chemistry and Molecular Diagnosis, Ministry of Education, Hebei University, Baoding, Hebei, 071002, China. Electronic address: xiaoqiao@hbu.edu.cn.

PMID: 32502865 DOI: 10.1016/j.ejmech.2020.112459

Abstract

In order to develop potent anticaner agents, a novel series of 3-(1H-indol-3-yl)-2,3,3a,4-tetrahydrothiochromeno[4,3-c]pyrazole derivatives were synthesized. Structures of all compounds were confirmed. MTT assay has been employed to study antiproliferative activity of these compounds with four human Cancer cell lines (MGC-803, Hela, MCF-7 and Bel-7404) and a normal cell line L929. Most of these compounds showed potential Anticancer activity and low cytotoxicity on normal cell in vitro. 7d and 7f showed the best Anticancer activity, whose IC₅₀ value is 15.43 μM and 20.54 μM towards MGC-803, respectively. Most of them exhibited Topoisomerase II selective inhibitory. Cleavage reaction assay and DNA unwinding assay showed that 7f was a nonintercalative Topo II catalytic inhibitor, which was consistent with the docking results. Laser scanning confocal microscopy system tracks the location of representative compounds 7d and 7f which can be abundantly entering the nucleus. In particular, the most potent compounds 7d and 7f were shown to be able to induce G2/M cell cycle arrest and Apoptosis in MGC-803 cells.

Keywords

Anticancer activity; Docking; Pyrazoline derivatives; Selectivity; Topoisomerase II.

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