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

Abstract

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.