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

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 - Feb 22 2021

All Science Journal Classification (ASJC) codes

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

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