Oxygen by Carbon Replacement at the Glycosidic Linkage Modulates the Sugar Conformation in Tn Antigen Mimics

Abstract

N-Acetylgalactosamine (GalNAc) α-O-linked to l-threonine (Thr) (Tn antigen) and several mimics of this Tn antigen have been synthesized to explore the impact of the underlying amino acid in the presentation mode of the carbohydrate moiety. The structural changes introduced in the Tn antigen mimics involve the replacement of the natural underlying Thr by non-natural amino acids while maintaining the α-O-glycosidic linkage of GalNAc or the substitution of this bond by α-C-glycosidic linkages. We also synthesized two bicyclic, conformationally restricted Tn antigen mimics. All of these compounds were subjected to a thorough conformational analysis in solution using NMR data, quantum mechanical (QM) calculations, and molecular dynamics simulations. Interestingly, in C-glycosides, the 1C4 chair conformation of the pyranose ring was predicted to be stable by QM calculations and experimentally supported by nuclear Overhauser effect cross-peaks and coupling constants observed in the NMR experiments.