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Rational design and synthesis of methyl-β-D-galactomalonyl phenyl esters as potent galectin-8N antagonists.

Galectin-8 is a β-galactoside recognising protein having an important role in the regulation of bone remodeling, cancer progression and metastasis. Methyl-β-D-galactopyranoside malonyl aromatic esters have been designed to target and engage with particular amino acid residues of the galectin-8N extended carbohydrate-binding site. The chemically synthesized compounds had in vitro binding affinity towards galectin-8N in the range of 5-33 μM, as evaluated by isothermal titration calorimetry. This affinity directly correlated with the compounds' ability to inhibit galectin-8-induced expression of chemokines and proinflammatory cytokines in SUM159 breast cancer cell line. X-ray crystallographic structure determination revealed that these monosaccharide-based compounds bind galectin-8N by engaging its unique arginine (Arg59), and simultaneously cross-linking to another (Arg45) located across the carbohydrate-binding site. This structure-based drug design approach has led to discovery of novel monosaccharide galactose-based antagonists, with the strongest binding compound (Kd 5.72 µM) being 7-fold tighter than the disaccharide lactose.