1H-1,2,3-triazol-1-yl thiodigalactoside derivatives as high affinity galectin-3 inhibitors

Bioorg Med Chem. 2010 Jul 15;18(14):5367-78. doi: 10.1016/j.bmc.2010.05.040. Epub 2010 May 20.

Abstract

Galactose C3-triazole derivatives were synthesized by Cu(I)-catalyzed cycloaddition between acetylenes and galactose C3-azido derivatives. Evaluation against galectin-3, 7, 8N (N-terminal) and 9N (N-terminal) revealed 1,4-disubstituted triazoles to be high-affinity inhibitors of galectin-3 with selectivity over galectin-7, 8N, and 9N. Conformational analysis of 1,4-di- and 1,4,5-tri-substituted galactose C3-triazoles suggested that a triazole C5-substituent interfered sterically with the galectin proteins, which explained their poor affinities compared to the corresponding 1,4-disubstituted triazoles. Introduction of two 1,4-disubstituted triazole moieties onto thiodigalactoside resulted in affinities down to 29 nM for galectin-3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalysis
  • Galectin 3 / antagonists & inhibitors*
  • Galectin 3 / metabolism*
  • Humans
  • Molecular Conformation
  • Structure-Activity Relationship
  • Thiogalactosides / chemical synthesis
  • Thiogalactosides / chemistry*
  • Thiogalactosides / pharmacology*
  • Triazoles / chemical synthesis
  • Triazoles / chemistry*
  • Triazoles / pharmacology*

Substances

  • Galectin 3
  • Thiogalactosides
  • Triazoles
  • thiodigalactoside