title: Reactions of 1,3-Diketones with a Dipeptide Isothiazolidin-3-one: Toward Agents That Covalently Capture Oxidized Protein Tyrosine Phosphatase 1B.
abstract: Protein tyrosine phosphatase 1B (PTP1B) is a validated therapeutic target for the treatment of type 2 diabetes; however, the enzyme has been classified by some as an "undruggable target". Here we describe studies directed toward the development of agents that covalently capture the sulfenyl amide "oxoform" of PTP1B generated during insulin signaling events. The sulfenyl amide residue found in oxidized PTP1B presents a unique electrophilic sulfur center that may be exploited in drug and probe design. Covalent capture of oxidized PTP1B could permanently disable the intracellular pool of enzyme involved in regulation of insulin signaling. Here, we employed a dipeptide model of oxidized PTP1B to investigate the nucleophilic capture of the sulfenyl amide residue by structurally diverse 1,3-diketones. All of the 1,3-diketones examined here reacted readily with the electrophilic sulfur center in the sulfenyl amide residue to generate stable covalent attachments. Several different types of products were observed, depending upon the substituents present on the 1,3-diketone. The results provide a chemical foundation for the development of agents that covalently capture the oxidized form of PTP1B generated in cells during insulin signaling events.
authors.affiliation: Department of Chemistry, University of Missouri , 125 Chemistry Building, Columbia, Missouri 65211, United States.
authors.forename: Kasi Viswanatharaju
authors.initials: KV
authors.lastname: Ruddraraju
authors.affiliation: Department of Chemistry, University of Missouri , 125 Chemistry Building, Columbia, Missouri 65211, United States.
authors.forename: Zachary D
authors.initials: ZD
authors.lastname: Parsons
authors.affiliation: Department of Chemistry, University of Missouri , 125 Chemistry Building, Columbia, Missouri 65211, United States.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Llufrio
authors.affiliation: Department of Chemistry, University of Missouri , 125 Chemistry Building, Columbia, Missouri 65211, United States.
authors.forename: Natasha L
authors.initials: NL
authors.lastname: Frost
authors.affiliation: Department of Chemistry, University of Missouri , 125 Chemistry Building, Columbia, Missouri 65211, United States.|Department of Biochemistry, University of Missouri , Columbia, Missouri 65211, United States.
authors.forename: Kent S
authors.initials: KS
authors.lastname: Gates
mesh_terms: D000577:Amides / Q000737:chemistry; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000201:enzymology; D004151:Dipeptides / Q000737:chemistry* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D007659:Ketones / Q000737:chemistry; D010084:Oxidation-Reduction; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D013844:Thiazoles / Q000737:chemistry*
chemical_list: D000577:Amides; D004151:Dipeptides; D004791:Enzyme Inhibitors; D007659:Ketones; D013844:Thiazoles; C512915:isothiazolidinone; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1