Synthesis and Affinity Evaluation of a Small Library of Bidentate Cholera Toxin Ligands: Towards Nonhydrolyzable Ganglioside Mimics

A small library of nonhydrolyzable mimics of GM1 ganglioside, featuring galactose and sialic acid as pharmacophoric carbohydrate residues, was synthesized and tested. All compounds were synthesized from readily available precursors using high‐performance reactions, including click chemistry protocols, and avoiding O‐glycosidic bonds. Some of the most active molecules also feature a point of further derivatization that can be used for conjugation with polyvalent aglycons. Their affinity towards cholera toxin was assessed by weak affinity chromatography, which allowed a systematic evaluation and selection of the best candidates. Affinity could be enhanced up to one or two orders of magnitude over the affinity of the individual pharmacophoric sugar residues. Toxic clean up: Novel cholera toxin ligands were identified by synthesizing and screening a library of bidentate molecules containing both a galactose and a sialic acid fragment (see figure).