Preparation of triazole-linked glycosylated α-ketocarboxylic acid derivatives as new PTP1B inhibitors.
The synthesis of triazole-linked glycosyl acetophenone, benzoic acid, and α-ketocarboxylic acid derivatives was readily achieved via Cu(I)-catalyzed azide-alkyne cycloaddition ('click' reaction) in excellent yields of 93-97%. Among the synthesized glycoconjugates, the triazolyl α-ketocarboxylic acids were identified as the most potent protein tyrosine phosphatase 1B (PTP1B) inhibitors with micromole-ranged IC(50) values and moderate-to-good selectivity over a panel of homologous PTPs including TCPTP (4.6-fold), LAR (>30-fold), SHP-1 (>30-fold) and SHP-2 (>30-fold). Moreover, a docking simulation was conducted to propose a plausible binding mode of the glucosyl α-ketocarboxylic acid triazole with the enzymatic target.
Key Laboratory for Advanced Material and Fine Chemicals, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, PR China.
Zhuo
Z
Song
Xiao-Peng
XP
He
Cui
C
Li
Li-Xin
LX
Gao
Zhao-Xia
ZX
Wang
Yun
Y
Tang
Juan
J
Xie
Jia
J
Li
Guo-Rong
GR
Chen
D002264:Carboxylic Acids / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006031:Glycosylation; D006801:Humans; D015394:Molecular Structure; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*
D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D014230:Triazoles; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1