Abstract
9-(5',5'-Difluoro-5'-phosphonopentyl)guanine (DFPP-G) and its hypoxanthine analogue (DFPP-H) were modified by introducing a methyl group to all possible positions of the linker connecting a purine and difluoromethylenephosphonic acid moiety to evaluate the effects of the methyl group on inhibition against purine nucleoside phosphorylase. The methyl group on the linker affected the inhibition in a positional-dependent manner. Inhibitory potency of alpha-methyl and beta-methyl-substituted analogues of DFPP-H increased by about 600- to 1000-fold upon converting to cyclopropane nucleotide analogue (+/-)-4.
Publication types
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Evaluation Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Clodronic Acid / analogs & derivatives
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Clodronic Acid / chemistry
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Clodronic Acid / pharmacology
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Cyclopropanes / chemistry
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Cyclopropanes / pharmacology
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Drug Design
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacology
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Fluorides / chemistry*
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Fluorides / pharmacology
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Guanine / analogs & derivatives*
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Guanine / chemical synthesis*
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Guanine / pharmacology
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Hypoxanthines / chemical synthesis*
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Hypoxanthines / pharmacology
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Kinetics
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Methylation
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Phosphoric Acids / chemistry*
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Phosphoric Acids / pharmacology
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Purine-Nucleoside Phosphorylase / antagonists & inhibitors*
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Purine-Nucleoside Phosphorylase / chemistry
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Purine-Nucleoside Phosphorylase / metabolism
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Structure-Activity Relationship
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Substrate Specificity
Substances
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9-(5',5'-difluoro-5'-phosphonopentyl)guanine
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Cyclopropanes
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Enzyme Inhibitors
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Hypoxanthines
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Phosphoric Acids
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Clodronic Acid
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difluoromethylene diphosphonate
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difluorophosphoric acid
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Guanine
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Purine-Nucleoside Phosphorylase
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Fluorides