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Microwave-assisted construction of triazole-linked amino acid-glucoside conjugates as novel PTP1B inhibitors

X. P. He, C. Li, X. P. Jin, Z. Song, H. L. Zhang, C. J. Zhu, Q. Shen, W. Zhang, L. Sheng, X. X. Shi, Y. Tang, J. Li, G. R. Chen and J. Xie New J. Chem., 2011, 35 (3), 622-631

There has been increasing interest in the development of protein tyrosine phosphatase 1B (PTP1B) inhibitors for the treatment of type 2 diabetes, obesity and breast cancer. We report here the identification of a series of mono-and bis-phenylalaninyl and tyrosinyl glucoside derivatives as novel PTP1B inhibitors. The designed compounds bearing one or two phenylalanine or tyrosine derivatives on the 6-, 2,3-, 2,6-, 3,4- and 4,6-positions of the glucosyl scaffolds were efficiently constructed via the microwave-assisted Cu(I)-catalyzed azide-alkyne cycloaddition in moderate-to-excellent yields. Successive biological assays identified these compounds as novel PTP1B inhibitors, with the 4,6-disubstituted tyrosinyl glucoside being the most potent. A kinetic study established that both mono-and bis-triazole-linked glycosyl acids act as typical competitive inhibitors whereas the bis-triazolyl ester that also exhibited inhibitory activity on PTP1B displayed a mixed-type inhibition pattern. Furthermore, docking simulation plausibly proposed the diverse binding modes of these compounds with the enzymatic target.

Type :

Publication

Dates :

Paru le 1 mars 2011

Informations complémentaires :

doi 10.1039/c0nj00835d