Journal
JACS AU
Volume 1, Issue 2, Pages 137-146Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacsau.0c00058
Keywords
ganglioside GM3; organic synthesis; C-glycoside; biological activity; conformational analysis
Categories
Funding
- PRIME [JP19gm5910018]
- CREST [JP18gm0710004]
- Platform Project for Supporting Drug Discovery and Life Science Research (BINDS) from AMED
- JSPS KAKENHI [18H04417, 18H02097]
- Asian Chemical Biology Initiative
- JSPS A3 Foresight Program
- RIKEN project fund
- Grants-in-Aid for Scientific Research [18H04417, 18H02097] Funding Source: KAKEN
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Glycoconjugates are important bio-molecules that regulate biological events in cells. This study successfully synthesized sialidase-resistant analogues of ganglioside GM3, demonstrating their inhibitory activity on EGF receptor autophosphorylation.
Glycoconjugates are an important class of bio-molecules 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 CF2- and CH2-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.
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