Unprecedented Citrinin Trimer Tricitinol B Functions as a Novel Topoisomerase IIα Inhibitor

Fifteen citrinin derivatives (1-4,6-16), including two unprecedented citrinin timers tricitrinols A (3) and B (4), were isolated from Penicillium citrinum HGY1-5. The six-membered ring A system is essential for the cytotoxicity of active dimers (1, 2, and 5) and trimers (3 and 4). Tricitrinol B (4) showed extensive cytotoxicity in 17 tumor cells with comparable low-micromolar IC50 values (1-10 mu M) and potential antimultidrug resistance capabilities. Tricitrinol B (4) induced cell apoptosis in HL60 and HCT116 cells via mainly extrinsic pathways and G2/M arrest. Further antitumor mechanism study and computational docking analysis indicated that tricitrinol B (4) works as an intercalating topoisomerase II alpha (topo II alpha) poison, which inhibits the enzyme activity of topo II alpha by interfering predominantly with the topo II alpha-mediated poststrand-passage deavage/religation equilibrium over with the prestrand-passage one and induced DNA damage. Tricitrinol B (4) represents a novel class of topo II alpha-inhibitory skeletons for developing new chemotherapeutic agents.