Discovery of N -Arylsulfonyl-Indole-2-Carboxamide Derivatives as Galectin-3 and Galectin-8 C-Terminal Domain Inhibitors.

Both galectin-3 and galectin-8 are involved in cell adhesion, migration, apoptosis, angiogenesis, and inflammatory processes by recognizing galactose-containing glycoproteins. Inhibiting galectin-3/8 activities is a potential treatment for cancer and tissue fibrosis. Herein, a series of novel N -arylsulfonyl-5-aryloxy-indole-2-carboxamide derivatives was disclosed as dual inhibitors toward galectin-3 and galectin-8 C-terminal domain with K d values of low micromolar level (Cpd 53 , gal-3: K d = 4.12 μM, gal-8C: K d = 6.04 μM; Cpd 57 , gal-3: K d = 12.8 μM, gal-8C: K d = 2.06 μM), which are the most potent and selective noncarbohydrate-based inhibitors toward gal-3/8 isoforms to date. The molecular docking investigations suggested that the unique amino acids Arg144 in galectin-3 and Ser213 in galectin-8C could contribute to their potency and selectivity. The scratch wound assay demonstrated that Cpd 53 and Cpd 57 were able to inhibit the MRC-5 lung fibroblast cells migration as well. This class of inhibitors could serve as a new starting point for further discovering structurally distinct gal-3 and gal-8C inhibitors to be used in cancer and tissue fibrosis treatment.