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.
© 2011 American Chemical Society
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anti-Bacterial Agents / chemistry
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Anti-Bacterial Agents / isolation & purification
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Anti-Bacterial Agents / pharmacology
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Antigens, Neoplasm / metabolism
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Apoptosis / drug effects
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Benzopyrans / chemistry*
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Benzopyrans / pharmacology*
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Biocatalysis / drug effects
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Blotting, Western
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Caspases / metabolism
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Cell Proliferation / drug effects*
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Cell Survival / drug effects
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Citrinin / chemistry*
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Citrinin / isolation & purification
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Citrinin / pharmacology*
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DNA Breaks, Double-Stranded / drug effects
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DNA Topoisomerases, Type II / metabolism
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DNA, Superhelical / chemistry
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DNA, Superhelical / metabolism
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DNA-Binding Proteins / antagonists & inhibitors*
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DNA-Binding Proteins / metabolism
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Dimerization
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Electrophoresis, Agar Gel
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Enzyme Activation / drug effects
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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HCT116 Cells
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HL-60 Cells
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Heterocyclic Compounds, 4 or More Rings / chemistry*
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Heterocyclic Compounds, 4 or More Rings / pharmacology*
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Humans
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Inhibitory Concentration 50
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Intercalating Agents / chemistry
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Intercalating Agents / pharmacology
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Models, Molecular
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Molecular Structure
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Penicillium / chemistry
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Poly(ADP-ribose) Polymerases / metabolism
Substances
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Anti-Bacterial Agents
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Antigens, Neoplasm
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Benzopyrans
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DNA, Superhelical
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DNA-Binding Proteins
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Enzyme Inhibitors
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Heterocyclic Compounds, 4 or More Rings
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Intercalating Agents
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tricitinol B
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Citrinin
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Poly(ADP-ribose) Polymerases
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Caspases
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DNA Topoisomerases, Type II