Abstract
Our laboratory recently reported the development of novel prodrug chemistry for the intracellular delivery of phosphotyrosine mimetics. This chemistry has now been adapted for the synthesis of a prodrug that delivers the nonhydrolyzable difluoromethylphosphonate moiety intracellularly. Activation of the prodrug generates a difluoromethylphosphonamidate anion that undergoes subsequent cyclization and hydrolysis with a t1/2 = 44 min. A highly potent and selective inhibitor of protein tyrosine phosphatase 1B (PTP1B) with a nanomolar Ki has been reported, but this bis(difluoromethylphosphonate) lacks potential utility due to its exceedingly low membrane permeability at physiological pH. A prodrug of this inhibitor has been synthesized and evaluated in a cell-based assay. The prodrug exhibits nanomolar PTP1B inhibitory activity in this assay, confirming the efficacy of intracellular phosphonate delivery using this prodrug approach.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Line, Tumor
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Cell Membrane Permeability
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Dipeptides / chemical synthesis*
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Dipeptides / chemistry
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Dipeptides / pharmacokinetics
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Humans
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Insulin / physiology
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Magnetic Resonance Spectroscopy
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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Organophosphorus Compounds / chemical synthesis*
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Organophosphorus Compounds / chemistry
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Organophosphorus Compounds / pharmacokinetics
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Phosphorylation
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Prodrugs / chemical synthesis*
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Prodrugs / chemistry
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Prodrugs / pharmacokinetics
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Protein Tyrosine Phosphatase, Non-Receptor Type 1
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Protein Tyrosine Phosphatases / antagonists & inhibitors*
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Receptor, Insulin / metabolism
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Signal Transduction
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Structure-Activity Relationship
Substances
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4-(O-nitrofurfuryl N-methyl-N-(4-chlorobutyl) phosphono(difluoromethyl))phenylacetyl-aspartyl-4-(O-nitrofurfuryl N-methyl-N-(4-chlorobutyl) phosphono(difluoromethyl))-N-(9-fluorenylmethoxycarbonyl)-phenylalanine amide
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Dipeptides
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Insulin
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Organophosphorus Compounds
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Prodrugs
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Receptor, Insulin
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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PTPN1 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 1
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Protein Tyrosine Phosphatases