Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 200, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2020.112459
Keywords
Pyrazoline derivatives; Topoisomerase II; Selectivity; Anticancer activity; Docking
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Funding
- Natural Science Foundation of Hebei Province [B2018201269]
- Scientific Research Foundation of Hebei Educational Committee [ZD2019060]
- National Natural Science Foundation of China [21675039]
- Young Talent of Hebei Province
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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 mu M and 20.54 mu M 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. (C) 2020 Elsevier Masson SAS. All rights reserved.
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