Synergy of triazolyl substituents at C1 and C3 of galactose for high-affinity and selective galectin-4C inhibition

Galectins are a family of carbohydrate-recognising proteins involved in regulation of cell adhesion and cell signaling, leading to roles in <i>e.g.</i> cancer progression, fibrosis, and ulcerative colitis. Glycomimetic galectin inhibitors based on different molecular scaffolds are known and have demonstrated effects from cell experiments to the clinic. Presented here is the synthesis and evaluation of 3-aryltriazolyl-C1-galactosyls leading to discovery of an unexpected synergy effect between C1 and C3 triazolyl substituents to give galectin-4C (C-terminal domain) inhibitors with affinities down to 9.5 μM and up to thirty-sevenfold selectivity for galectin-4C over other galectins. X-ray structural analysis of one inhibitor:galectin-4C complex revealed that both the C1 and C3 arene-substituents engage in interactions with the galectin-4C binding site. These molecules have potential as lead compounds towards discovery of galectin-4-targeting compounds addressing inflammatory conditions, such as inflammatory bowel disease and ulcerative colitis.