title: Synthesis, biological activity and structure-activity relationships of new benzoic acid-based protein tyrosine phosphatase inhibitors endowed with insulinomimetic effects in mouse C2C12 skeletal muscle cells.
abstract: Insulin resistance is a complex altered metabolic condition characterized by impaired insulin signaling and implicated in the pathogenesis of serious human diseases, such as diabetes, obesity, neurodegenerative pathologies. In pursuing our aim to identify new agents able to improve cellular insulin sensitivity, we have synthesized new 4-[(5-arylidene-4-oxo-2-phenylimino/oxothiazolidin-3-yl)methyl]benzoic acids (5, 8) and evaluated their inhibitory activity towards human protein tyrosine phosphatases PTP1B, LMW-PTP and TCPTP, enzymes which are involved in the development of insulin resistance. Compounds 5 and 8 showed from moderate to significant selectivity toward PTP1B over both the highly homologous TCPTP and the two isoforms of human LMW-PTP. In addition, most of the tested compounds selectively inhibited LMW-PTP IF1 over the isoform IF2. Docking studies into the active sites of PTP1B and LMW-PTP aided the rationalization of the observed PTP inhibitory profile. Moreover, most tested compounds were capable to induce the insulin metabolic pathway in mouse C2C12 skeletal muscle cells by remarkably stimulating both IRβ phosphorylation and 2-deoxyglucose cellular uptake.
authors.affiliation: Dipartimento di Scienze del Farmaco e dei Prodotti per la Salute, University of Messina, Polo Universitario dell'Annunziata, Viale SS. Annunziata, 98168 Messina, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Ottanà
authors.affiliation: Dipartimento di Scienze del Farmaco e dei Prodotti per la Salute, University of Messina, Polo Universitario dell'Annunziata, Viale SS. Annunziata, 98168 Messina, Italy. Electronic address: rmaccari@unime.it.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Maccari
authors.affiliation: Institute of Pharmacy, Department Pharmaceutical & Medicinal Chemistry, Freie Universität Berlin, 14195 Berlin, Germany; Institute of Chemistry and Biochemistry, Organic Chemistry, Freie University Berlin, 14195 Berlin, Germany.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Mortier
authors.affiliation: Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Sezione di Scienze Biochimiche, University of Firenze, Viale Morgagni 50, 50134 Firenze, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Caselli
authors.affiliation: Dipartimento di Scienze del Farmaco e dei Prodotti per la Salute, University of Messina, Polo Universitario dell'Annunziata, Viale SS. Annunziata, 98168 Messina, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Amuso
authors.affiliation: Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Sezione di Scienze Biochimiche, University of Firenze, Viale Morgagni 50, 50134 Firenze, Italy; Center for Research, Transfer and High Education DENOthe, Viale Pieraccini 6, 50139 Firenze, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Camici
authors.affiliation: Dipartimento di Scienze Chimiche, University of Messina, Viale F. Stagno d'Alcontres 31, 98166 Messina, Italy.
authors.forename: Archimede
authors.initials: A
authors.lastname: Rotondo
authors.affiliation: Institute of Pharmacy, Department Pharmaceutical & Medicinal Chemistry, Freie Universität Berlin, 14195 Berlin, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wolber
authors.affiliation: Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Sezione di Scienze Biochimiche, University of Firenze, Viale Morgagni 50, 50134 Firenze, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Paoli
mesh_terms: D000818:Animals; D019817:Benzoic Acid / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D051379:Mice; D062105:Molecular Docking Simulation; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D007328:Insulin; D019817:Benzoic Acid; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases
keywords: 2-DOG; 2-deoxyglucose; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; 4-[(5-Arylidene-4-oxo-2-phenylimino/oxothiazolidin-3-yl)methyl]benzoic acids; 5-Arylidene-4-thiazolidinone derivatives; Enzyme inhibitors; IR; Insulinomimetic effects; LMW-PTP; MALDI-TOF MS; MTT; Molecular docking; PTP; Protein tyrosine phosphatases; STAT; T cell protein tyrosine phosphatase; T2DM; TCPTP; insulin receptor; low molecular weight protein tyrosine phosphatase; matrix-assisted laser desorption/ionization time-of-flight mass; protein tyrosine phosphatase; signal transducer and activator of transcription; type 2 diabetes mellitus