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

• Published in: Journal of medicinal chemistry 2011-08, Vol.54 (16), p.5796-5810
• Main Authors: Du, Lin, Liu, Hong-Chun, Fu, Wei, Li, De-Hai, Pan, Qiu-Ming, Zhu, Tian-Jiao, Geng, Mei-Yu, Gu, Qian-Qun
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - isolation & purification; Anti-Bacterial Agents - pharmacology; Antigens, Neoplasm - metabolism; Apoptosis - drug effects; Benzopyrans - chemistry; Benzopyrans - pharmacology; Biocatalysis - drug effects; Blotting, Western; Caspases - metabolism; Cell Proliferation - drug effects; Cell Survival - drug effects; Citrinin - chemistry; Citrinin - isolation & purification; Citrinin - pharmacology; Dimerization; DNA Breaks, Double-Stranded - drug effects; DNA Topoisomerases, Type II - metabolism; DNA, Superhelical - chemistry; DNA, Superhelical - metabolism; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - metabolism; Electrophoresis, Agar Gel; Enzyme Activation - drug effects; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; HCT116 Cells; Heterocyclic Compounds, 4 or More Rings - chemistry; Heterocyclic Compounds, 4 or More Rings - pharmacology; HL-60 Cells; Humans; Inhibitory Concentration 50; Intercalating Agents - chemistry; Intercalating Agents - pharmacology; Models, Molecular; Molecular Structure; Penicillium - chemistry; Poly(ADP-ribose) Polymerases - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm200511x

Fifteen citrinin derivatives (1–4, 6–16), including two unprecedented citrinin trimers 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 μM) 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 IIα (topo IIα) poison, which inhibits the enzyme activity of topo IIα by interfering predominantly with the topo IIα-mediated poststrand-passage cleavage/religation equilibrium over with the prestrand-passage one and induced DNA damage. Tricitrinol B (4) represents a novel class of topo IIα-inhibitory skeletons for developing new chemotherapeutic agents.