Ganglioside GM3 Analogues Containing Monofluoromethylene-Linked Sialoside: Synthesis, Stereochemical Effects, Conformational Behavior, and Biological Activities.

Glycoconjugates are an important class of biomolecules that regulate numerous biological events in cells. However, these complex, medium-size molecules are metabolically unstable, which hampers detailed investigations of their functions as well as their potential application as pharmaceuticals. Here we report sialidase-resistant analogues of ganglioside GM3 containing a monofluoromethylene linkage instead of the native -sialoside linkage. Stereoselective synthesis of -linked disaccharides and kinetically controlled Au(I)-catalyzed glycosylation efficiently furnished both stereoisomers of -linked as well as - and -linked GM3 analogues. Like native GM3, the -linked GM3 analogues inhibited the autophosphorylation of epidermal growth factor (EGF) receptor induced by EGF . Assay of the proliferation-enhancing activity toward Had-1 cells together with NMR-based conformational analysis showed that the ()--linked GM3 analogue with -gauche conformation is the most potent of the synthesized compounds. Our findings suggest that -anomeric conformation is important for the biological functions of GM3.