Abstract
Fumagillin and ovalicin constitute a family of structurally related natural products that possess antiangiogenic activity. We report the synthesis of a new fumagillin analogue, fumagalone, in which the spiroepoxide group is replaced with an aldehyde. Fumagalone inhibits type 2 methionine aminopeptidase (MetAP2) with IC(50) = 8 microM and endothelial cell proliferation with IC(50) = 52 nM. With dialysis and competition assays, it was unambiguously demonstrated that binding of fumagalone to MetAP2 is reversible.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Aminopeptidases / antagonists & inhibitors*
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Angiogenesis Inhibitors / chemical synthesis*
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Angiogenesis Inhibitors / chemistry
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Angiogenesis Inhibitors / pharmacology
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Animals
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Cattle
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Cell Division / drug effects
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Cyclohexanes
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Cyclohexanones / chemical synthesis*
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Cyclohexanones / chemistry
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Cyclohexanones / pharmacology
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Endothelium, Vascular / cytology
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Endothelium, Vascular / drug effects
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Epoxy Compounds / chemical synthesis*
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Epoxy Compounds / chemistry
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Epoxy Compounds / pharmacology
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Fatty Acids, Unsaturated / chemical synthesis*
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Fatty Acids, Unsaturated / chemistry
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Fatty Acids, Unsaturated / pharmacology
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In Vitro Techniques
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Metalloendopeptidases / antagonists & inhibitors*
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Protein Binding
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Sesquiterpenes
Substances
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Angiogenesis Inhibitors
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Cyclohexanes
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Cyclohexanones
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Epoxy Compounds
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Fatty Acids, Unsaturated
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Sesquiterpenes
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fumagalone
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fumagillin
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Aminopeptidases
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methionine aminopeptidase 2
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Metalloendopeptidases