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

Autor: Gerhard Wolber, Adriana Carol Eleonora Graziano, Ilenia Adornato, Venera Cardile, Rosaria Ottanà, Rosanna Maccari, Archimede Rotondo, Paolo De Paoli, Alexandra Naß, Giulia Lori
Rok vydání: 2017
Předmět:
0301 basic medicine
Protein Conformation
Stereochemistry
Allosteric regulation
Anti-Inflammatory Agents
protein tyrosine phosphatases
enzyme inhibitors
insulinomimetic effects
anti-inflammatory activity
molecular docking
5-arylidene-4-thiazolidinone derivatives
Protein tyrosine phosphatase
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Allosteric Regulation
Drug Discovery
Humans
Insulin
Computer Simulation
Protein kinase B
Benzoic acid
Protein Tyrosine Phosphatase
Non-Receptor Type 1
Pharmacology
chemistry.chemical_classification
biology
Chemistry
Organic Chemistry
Hep G2 Cells
General Medicine
Benzoic Acid
In vitro
Kinetics
Insulin receptor
030104 developmental biology
Enzyme
Biochemistry
Docking (molecular)
Drug Design
030220 oncology & carcinogenesis
biology.protein
Peptidomimetics
Zdroj: European Journal of Medicinal Chemistry. 127:840-858
ISSN: 0223-5234
DOI: 10.1016/j.ejmech.2016.10.063
Popis: 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.
Databáze: OpenAIRE
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