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

Basic Information

ID: ALA4196027

Journal: Eur J Med Chem

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

Authors: Wu G, Qi X, Mo X, Yu G, Wang Q, Zhu T, Gu Q, Liu M, Li J, Li D.

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.

CiteXplore: 29466776

DOI: 10.1016/j.ejmech.2018.02.041

Patent ID: ┄