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

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.