title: Unprecedented citrinin trimer tricitinol B functions as a novel topoisomerase IIα inhibitor.
abstract: 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 IC(50) 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.
authors.affiliation: Key laboratory of Marine Drugs, the Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, PR China.
authors.forename: Lin
authors.initials: L
authors.lastname: Du
authors.forename: Hong-Chun
authors.initials: HC
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Fu
authors.forename: De-Hai
authors.initials: DH
authors.lastname: Li
authors.forename: Qiu-Ming
authors.initials: QM
authors.lastname: Pan
authors.forename: Tian-Jiao
authors.initials: TJ
authors.lastname: Zhu
authors.forename: Mei-Yu
authors.initials: MY
authors.lastname: Geng
authors.forename: Qian-Qun
authors.initials: QQ
authors.lastname: Gu
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001578:Benzopyrans / Q000737:chemistry* / Q000494:pharmacology*; D055162:Biocatalysis / Q000187:drug effects; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002953:Citrinin / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004278:DNA, Superhelical / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019281:Dimerization; D004587:Electrophoresis, Agar Gel; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D045325:HCT116 Cells; D018922:HL-60 Cells; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007364:Intercalating Agents / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D010407:Penicillium / Q000737:chemistry; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D000951:Antigens, Neoplasm; D001578:Benzopyrans; D004278:DNA, Superhelical; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; D007364:Intercalating Agents; C568462:tricitinol B; D002953:Citrinin; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D004250:DNA Topoisomerases, Type II