title: Synthesis and cell-based activity of a potent and selective protein tyrosine phosphatase 1B inhibitor prodrug.
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.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology and the Cancer Center, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: Irene G
authors.initials: IG
authors.lastname: Boutselis
authors.forename: Xiao
authors.initials: X
authors.lastname: Yu
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
authors.forename: Richard F
authors.initials: RF
authors.lastname: Borch
mesh_terms: D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D007328:Insulin / Q000502:physiology; D009682:Magnetic Resonance Spectroscopy; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D010766:Phosphorylation; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: C518312:4-(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; D004151:Dipeptides; D007328:Insulin; D009943:Organophosphorus Compounds; D011355:Prodrugs; D011972:Receptor, Insulin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases