Glycomimetic inhibitors of tandem-repeat galectins: Simple and efficient

Bioorg Chem. 2024 Apr:145:107231. doi: 10.1016/j.bioorg.2024.107231. Epub 2024 Feb 20.

Abstract

The binding of human galectins by glycomimetic inhibitors is a promising therapeutic approach. The structurally distinct group of tandem-repeat galectins has scarcely been studied so far, and there is hardly any knowledge on their ligand specificity or their inhibitory potential, particularly concerning non-natural carbohydrates. Here, we present the synthesis of a library of seven 3-O-disubstituted thiodigalactoside-derived glycomimetics and their affinity to two tandem-repeat galectins, Gal-8 and Gal-9. The straightforward synthesis of these glycomimetics involved dibutyltin oxide-catalyzed 3,3́-O-disubstitution of commercially available unprotected thiodigalactoside, and conjugation of various aryl substituents by copper-catalyzed Huisgen azide-alkyne cycloaddition (CuAAC). The inhibitory potential of the prepared glycomimetics for Gal-8 and Gal-9 was assessed, and compared with the established galectins Gal-1 and Gal-3. The introduction of C-3 substituents resulted in an over 40-fold increase in affinity compared with unmodified TDG. The structure-affinity relations within the studied series were discussed using molecular modeling. Furthermore, the prepared glycomimetics were shown to scavenge Gal-8 and Gal-9 from the surface of cancer cells. This pioneering study on the synthetic inhibitors especially of Gal-9 identified lead compounds that may be used in further biomedical research.

Keywords: Glycomimetic; Molecular modeling; Structure-affinity relationship; Tandem-repeat galectin; Thiodigalactoside.

MeSH terms

  • Carbohydrates / chemistry
  • Galectins* / metabolism
  • Humans
  • Protein Binding
  • Thiogalactosides* / chemistry

Substances

  • thiodigalactoside
  • Galectins
  • Thiogalactosides
  • Carbohydrates