Tuning the preference of thiodigalactoside- and lactosamine-based ligands to galectin-3 over galectin-1

Inhibitors for Galectin-1 and -3 were synthesized from thiodigalactoside and lactosamine by derivatization of the galactose C3. Introduction of 4-phenyl-1H-1,2,3-triazol-1-yl substituents at the thiodigalactoside C3 by CuAAC, targeting arginine-arene interactions, increased the affinity to 13 nM but yielded little selectivity. The bulkier 4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-yl substituent, however, increased the preference for Galectin-3 over Galectin-1 to more than 200-fold. Modeling showed more arginine-arene interactions for Galectin-3 than for Galectin-1. Introducing 4-phenoxyaryl groups on lactosamine had a similar effect.