Structure-based discovery of cytotoxic dimeric tetrahydroxanthones as potential topoisomerase I inhibitors from a marine-derived fungus

European Journal of Medicinal Chemistry
Guangwei WuDehai Li

Abstract

DNA topoisomerase I (Topo I) is an important anticancer drug target, and xanthone dimers are considered to be a new kind of Topo I inhibitor chemotypes. Based on the characteristics of dimeric xanthone structures, five new dimeric xanthones (1-5) and two known SAD isomers (6 and 7) were isolated from the mangrove-derived fungus Aspergillus vericolor. The absolute configurations of compounds 1-7, entailing both central and axial chirality elements, were established by a combination of ECD comparison, chemical conversions, and biogenetic considerations. Compounds 1-7 possessed high structural diversity and exhibited cytotoxicity at different levels. The selected new compounds 1, 2, and 5 showed Topo I inhibition properties and the most potent compound 1, an atropisomer of compound 2, was confirmed to inhibit Topo I-mediated DNA relaxation by targeting Topo I, thereby, arresting the cell cycle process and inducing necrosis in cancer cells. Molecular docking studies showed that compound 1 could bind DNA by π-π interaction and DNA Topo I by hydrogen bonds to form a ternary complex.

Citations

Feb 7, 2020·Natural Product Reports·Anthony R CarrollMichèle R Prinsep
Jul 18, 2018·Marine Drugs·Florbela Pereira, Joao Aires-de-Sousa
Sep 21, 2021·Journal of Agricultural and Food Chemistry·Xiaoping PengHongxiang Lou
Sep 24, 2021·Journal of Natural Products·Friederike LünneSvetlana A Kalinina
Oct 9, 2021·Natural Product Reports·Senhua ChenZhigang She
Jan 15, 2022·Journal of Natural Products·Hai-Yan CaoYun-Bao Liu

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