New CD1d agonists

Synthesis and biological activity of 6″-triazole-substituted α-galactosyl ceramides

Peter J. Jervis, Lisa M. Graham, Erin L. Foster, Liam R. Cox, Steven A. Porcelli, Gurdyal S. Besra

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Huisgen [3+2] dipolar cycloaddition of 6″-azido-6″-deoxy- α-galactosyl ceramide 11 with a range of alkynes (or a benzyne precursor) yielded a series of triazole-containing α-galactosyl ceramide (α-GalCer) analogues in high yield. These α-GalCer analogues and the precursor azide 11 were tested for their ability to activate iNKT cells and stimulate IL-2 cytokine secretion in vitro, and IFN-γ and IL-4 cytokine secretion in vivo. Some of these analogues, specifically 11, 12b, 12f and 13, were more potent IL-2 stimulators than the prototypical CD1d agonist, α-GalCer 1. In terms of any cytokine bias, most of the triazole-containing analogues exhibited a small Th2 cytokine-biasing response relative to that shown by α-GalCer 1. In contrast, the cycloaddition precursor, namely azide 11, provided a small Th1 cytokine-biasing response.

Original languageEnglish (US)
Pages (from-to)4348-4352
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number13
DOIs
StatePublished - Jul 1 2012

Fingerprint

Galactosylceramides
Triazoles
Bioactivity
Cytokines
Azides
Cycloaddition
Cycloaddition Reaction
Interleukin-2
Natural Killer T-Cells
Alkynes
Interleukin-4

Keywords

  • α-GalCer
  • CD1d
  • Click chemistry
  • iNKT cell
  • Triazole

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

New CD1d agonists : Synthesis and biological activity of 6″-triazole-substituted α-galactosyl ceramides. / Jervis, Peter J.; Graham, Lisa M.; Foster, Erin L.; Cox, Liam R.; Porcelli, Steven A.; Besra, Gurdyal S.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 22, No. 13, 01.07.2012, p. 4348-4352.

Research output: Contribution to journalArticle

Jervis, Peter J. ; Graham, Lisa M. ; Foster, Erin L. ; Cox, Liam R. ; Porcelli, Steven A. ; Besra, Gurdyal S. / New CD1d agonists : Synthesis and biological activity of 6″-triazole-substituted α-galactosyl ceramides. In: Bioorganic and Medicinal Chemistry Letters. 2012 ; Vol. 22, No. 13. pp. 4348-4352.
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