Synthesis of sialic acid derivatives as ligands for the myelin-associated glycoprotein (MAG)

The trisaccharide substructure 13 of the ganglioside GQ1bα shows a remarkable affinity for the myelin-associated glycoprotein (MAG). In the search for structurally simplified and pharmacokinetically improved mimics of 13, sialosides with modifications at the reducing and non-reducing end were synthesized. The biological evaluation of mimics 12a–o was performed in a competitive target-based assay. It was found that the relative inhibitory potency (rIP) of antagonist 12h was enhanced by more than 1000-fold in comparison to the reference trisaccharide 13, despite the former having a much simpler structure. In addition, the sialic acid derivatives, for example, 12h, have clearly improved pharmacokinetic properties due to the presence of aromatic moieties, a lower molecular weight, and a reduced number of polar hydroxy functions compared to the reference compound 13.

Simplified mimics of trisaccharide 13, where the core disaccharide Galβ(1–3)GalNAc was replaced with a benzyl group, and the non-reducing end substituted with a para-chloro-benzamide, were synthesized and biologically evaluated to produce a 1000-fold more active inhibitor of the myelin-associated glycoprotein (MAG).Figure optionsDownload as PowerPoint slide