Screening for galectin-3 inhibitors from synthetic lacto-N-biose libraries using microscale affinity chromatography coupled to mass spectrometry

The synthesis and screening of two beta-D-Galp-(1-3)-beta-D-GlcpN ( lacto-N-biose) disaccharide libraries are reported. Solution-phase synthetic modifications at the HO-2' and NH positions were performed in an effort to enhance the affinity toward galectin-3, a galactose-binding protein involved in tumor metastasis, apoptosis, and inflammation. The libraries were screened for galectin-3 binding by microscale frontal affinity chromatography coupled to mass spectrometry ( FAC/MS) allowing for rapid ranking of the different inhibitors and the determination of the galectin-3 binding K-d's. Compounds bearing a hydrophobic substituent on the NH group showed the highest affinity for the lectin. The N-naphthoyl derivative ( K-d = 10.6 mu M) was the best inhibitor with a 7 times increased affinity as compared to the N-acetyl parent compound ( K-d = 73.3 mu M).