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

Abstract

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 O -sialoside linkage. Stereoselective synthesis of CHF -linked disaccharides and kinetically controlled Au(I)-catalyzed glycosylation efficiently furnished both stereoisomers of CHF -linked as well as CF 2 - and CH 2 -linked GM3 analogues. Like native GM3, the C -linked GM3 analogues inhibited the autophosphorylation of epidermal growth factor (EGF) receptor induced by EGF in vitro . Assay of the proliferation-enhancing activity toward Had-1 cells together with NMR-based conformational analysis showed that the ( S )- CHF -linked GM3 analogue with exo -gauche conformation is the most potent of the synthesized compounds. Our findings suggest that exo -anomeric conformation is important for the biological functions of GM3.

Advanced Chemical Methods for Stereoselective Sialylation and Their Applications in Sialoglycan Syntheses

“…This strategy was first developed by Hashimoto et al [77] . and later employed for ganglioside synthesis by several groups, [78] including ours [79] . We have, for the first time, described this technique as a “glucosylceramide (GlcCer) cassette” strategy (Scheme 31B) [80]…”

“…A separately synthesized sialoglycan donor was then coupled with the glucosyl Cer acceptor to afford the complete ganglioside skeleton. This strategy was first developed by Hashimoto et al [77] and later employed for ganglioside synthesis by several groups, [78] including ours. [79] We have, for the first time, described this technique as a "glucosylceramide (GlcCer) cassette" strategy (Scheme 31B).…”

Cellular and Molecular Engineering of Glycan Sialylation in Heterologous Systems

“…Free carbohydrate molecules with unnatural moieties or an unusual branching pattern can be physiologically active yet metabolically stable, making them potentially useful for in vivo applications [ 114 , 115 ]. They may also be included in a glycan array to study glycoenzymes and glycan binding proteins [ 116 ].…”

β-Glycosyl Trifluoroborates as Precursors for Direct α-C-Glycosylation: Synthesis of 2-Deoxy-α-C-glycosides

“…In particular, C -glycosides exhibit high structural similarity to native glycans. , For example, we recently demonstrated that C -glycoside analogues of ganglioside GM3, especially molecules with a CHF -glycoside linkage, exhibit greater biological activity at the cell level than analogues with a CH 2 - or a CF 2 -linkage. Furthermore, their conformation is similar to that of native GM3 . However, despite many reports of synthetic methodology for C -glycosides, there are few efficient strategies for directly forming a C -glycosidic linkage (direct C-glycosylation) via intermolecular coupling reaction, like a standard O-glycosylation reaction.…”

“…Furthermore, their conformation is similar to that of native GM3. 3 However, despite many reports of synthetic methodology for C-glycosides, there are few efficient strategies for directly forming a C-glycosidic linkage (direct C-glycosylation) via intermolecular coupling reaction, like a standard Oglycosylation reaction.…”