Abstract
To study the relevance of the terminal alpha,beta-unsaturated gamma-methyl-gamma-lactone moiety of the antitumoral acetogenins of Annonaceae for potent mitochondrial complex I inhibition, we have prepared a series of semisynthetic acetogenins with modifications only in this part of the molecule, from the natural rolliniastatin-1 (1) and cherimolin-1 (2). Some of the hydroxylated derivatives (1b, 1d and 1e) in addition to two infrequent natural beta-hydroxy gamma-methyl gamma-lactone acetogenins, laherradurin (3) and itrabin (4), are more potent complex I inhibitors than any other known compounds.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacology
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Cattle
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Electron Transport Complex I
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Furans / chemical synthesis
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Furans / chemistry*
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Furans / pharmacology
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Lactones / chemical synthesis
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Lactones / chemistry*
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Lactones / pharmacology
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Magnoliopsida / chemistry
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Mitochondria, Heart / drug effects
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Mitochondria, Heart / enzymology*
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Molecular Structure
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Multienzyme Complexes / antagonists & inhibitors
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Multienzyme Complexes / metabolism
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NADH, NADPH Oxidoreductases / antagonists & inhibitors*
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NADH, NADPH Oxidoreductases / metabolism
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Submitochondrial Particles / drug effects
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Submitochondrial Particles / enzymology
Substances
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Antineoplastic Agents
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Furans
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Lactones
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Multienzyme Complexes
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cherimolin-1
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isomurisolenin
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itrabin
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laherradurin
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bullatacin
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NADH oxidase
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NADH, NADPH Oxidoreductases
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Electron Transport Complex I