Synthesis and cell-based activity of a potent and selective protein tyrosine phosphatase 1B inhibitor prodrug.
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.
Boutselis
Irene G
IG
Department of Medicinal Chemistry and Molecular Pharmacology and the Cancer Center, Purdue University, West Lafayette, Indiana 47907, USA.
Yu
Xiao
X
Zhang
Zhong-Yin
ZY
Borch
Richard F
RF
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
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