title: Discovery of 4-[(5-arylidene-4-oxothiazolidin-3-yl)methyl]benzoic acid derivatives active as novel potent allosteric inhibitors of protein tyrosine phosphatase 1B: In silico studies and in vitro evaluation as insulinomimetic and anti-inflammatory agents.
abstract: New 4-{[5-arylidene-2-(4-fluorophenylimino)-4-oxothiazolidin-3-yl]methyl}benzoic acids (5) and 2-thioxo-4-thiazolidinone analogues (6) were synthesised as a part of a continuing search for new inhibitors of protein tyrosine phosphatase 1B (PTP1B), an enzyme which is implicated in metabolic disorders and inflammatory signaling. Most of the tested compounds were shown to be potent PTP1B inhibitors. Moreover, their inhibition mechanism was markedly influenced by the substituents in the positions 2 and 5, as kinetic studies indicated. Docking experiments suggested that certain derivatives 5 and 6 may efficiently fit into an allosteric site positioned between the β-sheet including Leu71 and Lys73 and a lipophilic pocket closed by the loop consisting of Pro210 to Leu 204. In cellular assays, several of these new 4-thiazolidinone derivatives showed insulinomimetic and anti-inflammatory properties. Out of them, compound 5b exhibited the most promising profile, being able to promote the activation of both insulin receptor and downstream Akt protein as well as to increase 2-deoxyglucose cellular uptake. Interestingly, compound 5b was also able to interrupt critical events in inflammatory signaling.
authors.affiliation: Department of Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali, University of Messina, Polo Universitario dell'Annunziata, Viale SS. Annunziata, 98168 Messina, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Ottanà
authors.affiliation: Department of 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
authors.affiliation: Institute of Pharmacy, Computer-Aided Molecular Design, Freie Universitaet Berlin, Koenigin-Luisestr. 2+4, 14195 Berlin, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Naß
authors.affiliation: Department of Scienze Biomediche Sperimentali e Cliniche, Sezione di Scienze Biochimiche, University of Firenze, Viale Morgagni 50, 50134 Firenze, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Lori
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Via S. Sofia, 64, 95125 Catania, Italy.
authors.forename: Venera
authors.initials: V
authors.lastname: Cardile
authors.affiliation: Department of Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali, University of Messina, Polo Universitario dell'Annunziata, Viale SS. Annunziata, 98168 Messina, Italy.
authors.forename: Ilenia
authors.initials: I
authors.lastname: Adornato
authors.affiliation: Department of Scienze Biomediche, Odontoiatriche e delle Immagini Morfologiche e Funzionali, Università degli Studi di Messina - sez. SASTAS - Polo Universitario dell'Annunziata, Viale SS. Annunziata, 98168 Messina, Italy.
authors.forename: Archimede
authors.initials: A
authors.lastname: Rotondo
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Via S. Sofia, 64, 95125 Catania, Italy.
authors.forename: Adriana Carol Eleonora
authors.initials: ACE
authors.lastname: Graziano
authors.affiliation: Institute of Pharmacy, Computer-Aided Molecular Design, Freie Universitaet Berlin, Koenigin-Luisestr. 2+4, 14195 Berlin, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wolber
authors.affiliation: Department of Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali, 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
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D019817:Benzoic Acid / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D003198:Computer Simulation; D015195:Drug Design; D056945:Hep G2 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007700:Kinetics; D057786:Peptidomimetics / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D007328:Insulin; D057786:Peptidomimetics; D019817:Benzoic Acid; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1
keywords: 5-Arylidene-4-thiazolidinone derivatives; Anti-inflammatory activity; Enzyme inhibitors; Insulinomimetic effects; Molecular docking; Protein tyrosine phosphatases