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

Go Hirai*, Marie Kato, Hiroyuki Koshino, Eri Nishizawa, Kana Oonuma, Eisuke Ota, Toru Watanabe, Daisuke Hashizume, Yuki Tamura, Mitsuaki Okada, Taeko Miyagi, Mikiko Sodeoka

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)137-146
Number of pages10
JournalJournal of the American Chemical Society
Volume1
Issue number2
DOIs
Publication statusPublished - 2021 Feb 22
Externally publishedYes

Keywords

  • C-glycoside
  • biological activity
  • conformational analysis
  • ganglioside GM3
  • organic synthesis

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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