Low Micromolar Inhibitors of Galectin-3 Based on 3′-Derivatization of N-Acetyllactosamine

A strategy for generating potential galectin inhibitors was devised based on derivatization at the C‐3′ atom in 3′‐amino‐N‐acetyllactosamine by using structural knowledge of the galectin carbohydrate recognition site. A collection of 12 compounds was prepared by N‐acylations or N‐sulfonylations. Hydrophobic tagging of the O‐3 atom in the N‐acetylglucosamine residue with a stearic ester allowed rapid and simple product purification. The compounds were screened in a galectin‐3 binding assay and three compounds with significantly higher inhibitory activities compared to the parent N‐acetyllactosaminide were found. These three best inhibitors all carried an aromatic amide at the C‐3′ position of the galactose moiety, which indicates that favorable interactions were formed between the aromatic group and galectin‐3. The best inhibitor had an IC50 value (4.4 μM) about 50 times better than the parent N‐acetyllactosaminide, which implies that it has potential as a valuable tool for studying galectin‐3 biological functions and also as a lead compound for the development of galectin‐3‐blocking pharmaceuticals. Potential lead compounds for the design of novel types of anti‐inflammatory and anticancer agents and valuable research tools to be applied in various cell culture models could be provided by the potent galectin‐3 inhibitors (such as 1; IC50=4.4 μM against galectin‐3) discovered by derivatization of 3′‐amino‐N‐acetyllactosamine. There is strong evidence that galectins, a family of β‐galactoside‐binding proteins, modulate cell signaling, adhesion, and apoptosis, but their precise mechanisms of action remain elusive.