Preparation of triazole-linked glycosylated α-ketocarboxylic acid derivatives as new PTP1B inhibitors

Carbohydr Res. 2011 Jan 3;346(1):140-5. doi: 10.1016/j.carres.2010.10.023. Epub 2010 Oct 30.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carboxylic Acids / chemistry*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Glycosylation
  • Humans
  • Molecular Structure
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Triazoles / chemistry*

Substances

  • Carboxylic Acids
  • Enzyme Inhibitors
  • Triazoles
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1