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

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• 作者：Rosaria Ottan脿 ; Rosanna Maccari ; J茅r茅mie Mortier ; Anna Caselli ; Simona Amuso ; Guido Camici ; Archimede Rotondo ; Gerhard Wolber ; Paolo Paoli
• 关键词：Protein tyrosine phosphatases ; Enzyme inhibitors ; Insulinomimetic effects ; Molecular docking ; 5-Arylidene-4-thiazolidinone derivatives ; 4-[(5-Arylidene-4-oxo-2-phenylimino/oxothiazolidin-3-yl)methyl]benzoic acids
• 刊名：European Journal of Medicinal Chemistry
• 出版年：7 January, 2014
• 年：2014
• 卷：71
• 期：Complete
• 页码：112-127
• 全文大小：2584 K

文摘

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 IR尾 phosphorylation and 2-deoxyglucose cellular uptake.