Open AccessGanglioside GM3 Analogues Containing Monofluoromethylene-Linked Sialoside: Synthesis, Stereochemical Effects, Conformational Behavior, and Biological Activities
Author(s) -
Go Hirai,
Masamichi Κato,
Hiroyuki Koshino,
Eri Nishizawa,
Kana Oonuma,
Eisuke Ota,
Tôru Watanabe,
Daisuke Hashizume,
Yuki Tamura,
Masakazu Okada,
Taeko Miyagi,
Mikiko Sodeoka
Publication year - 2020
Publication title -
jacs au
Language(s) - English
Resource type - Journals
ISSN - 2691-3704
DOI - 10.1021/jacsau.0c00058
Subject(s) - glycoconjugate , chemistry , ganglioside , stereochemistry , biological activity , glycosylation , biochemistry , glycosyltransferase , in vitro , anomer , epidermal growth factor , glycolipid , receptor , enzyme
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.