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A unique and rapid approach toward the efficient development of novel protein tyrosine phosphatase (PTP) inhibitors based on 'clicked' pseudo-glycopeptides

Yang, J. W. ; He, X. P. ; Li, C. ; Gao, L. X. ; Sheng, L. ; Xie, J. ; Shi, X. X. ; Tang, Y. ; Li, J. ; Chen, G. R. ; Bioorganic & Medicinal Chemistry Letters, 2011, 21(4), 1092-1096

There has been considerable interest in the development of protein tyrosine phosphatase (PTP) inhibitors since many of the PTP members are tightly associated with major human diseases including autoimmune disorders, diabetes and cancer. We report here a unique and rapid approach toward the development of novel PTP inhibitor entities based on triazolyl pseudo-glycopeptides. By employing microwave-accelerated Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC or 'click reaction'), a series of triazole-linked serinyl, threoninyl, phenylalaninyl and tyrosinyl 1-O-gluco- or galactosides have been efficiently synthesized in high yields within only similar to 30 min. Successive biological assay identified these glycopeptidotriazoles as favorable PTP1B and CDC25B inhibitors with selectivity over TCPTP, LAR, SHP-1 and SHP-2. Both the structural diversity of the amino acid (Ser, Thr, Phe and Tyr) introduced and the epimeric identity (Glc or Gal) on monosaccharide scaffold were determined to impact the corresponding inhibitory activity and selectivity. In addition, the benzylated sugar scaffold was demonstrated to act as a crucial role for enhancing the binding affinity of the inhibitors with the targeted PTP. Docking simulation was eventually conducted to propose plausible binding modes of this compound series with PTP1B and CDC25B. Our approach readily realized from naturally abundant raw materials (sugar and amino acid) and via facile, regioselective and expeditious synthetic method (microwave-assisted click reaction) might provide new insights toward the 'click' fabrication of structurally diverse PTP inhibitors. (c) 2010 Elsevier Ltd. All rights reserved.

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Publication

Dates :

Paru le 31 janvier 2011

Informations complémentaires :

doi 10.1016/j.bmcl.2010.12.126