Abstract
1,1-Difluoro-2-(tetrahydro-3-furanyl)ethylphosphonic acids cis-3 and trans-3 possessing a N9-purinylmethyl functionality at the ring were synthesized and tested as "multi-substrate analogue" inhibitors for purine nucleoside phosphorylases. Radical cyclization of allyic alpha,alpha-difluorophosphonate (E)-7 was applied to construct the alpha,alpha-difluorophosphonate-functionalized tetrahydrofuranyl moiety. The IC50 values of cis-3 and trans-3 for human erythrocyte PNP-catalyzed phosphorylation of inosine were determined to be 88 and 320 nM, respectively. The stereochemistry of the inhibitors was found to affect significantly the inhibitory potency.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / pharmacology
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / pharmacology
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Erythrocytes / enzymology
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Fluorine Compounds / chemical synthesis*
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Fluorine Compounds / pharmacology
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Furans / chemical synthesis*
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Furans / pharmacology
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Gram-Positive Asporogenous Rods / enzymology
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Humans
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Inosine / metabolism
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Molecular Structure
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Organophosphonates / chemical synthesis*
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Organophosphonates / pharmacology
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Phosphorylation
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Purine-Nucleoside Phosphorylase / antagonists & inhibitors*
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Purines / chemical synthesis*
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Purines / pharmacology
Substances
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1,1-difluoro-2-(tetrahydro-3-furanyl)ethylphosphonic acid
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Antineoplastic Agents
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Enzyme Inhibitors
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Fluorine Compounds
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Furans
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Organophosphonates
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Purines
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Inosine
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Purine-Nucleoside Phosphorylase