Synthesis
and Biological Evaluation of α‑Galactosylceramide
Analogues with Heteroaromatic Rings and Varying Positions of a Phenyl
Group in the Sphingosine Backbone
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Abstract
We
designed and synthesized seven α-GalCer analogues with
a pyrazole moiety and varying positions of a phenyl group in the sphingosine
backbone to polarize cytokine secretion. On the basis of in vitro
and in vivo biological evaluations, we found that analogue <b>5</b> induced greater polarization toward Th2 and greater secretion of
the immunomodulatory cytokine, IL-4, over secretion of pro-inflammatory
cytokines, IFN-γ and IL-17. Treatment of a single dose of analogue <b>5</b> markedly ameliorated disease pathogenesis in an animal model
of an inflammatory demyelinating disease of the central nervous system,
compared to that of KRN7000 (<b>1</b>). Therefore, this new
α-GalCer analogue <b>5</b> is a novel iNKT ligand that
stimulates the selective secretion of anti-inflammatory cytokines
and regulates autoimmune diseases by reducing Th1 and Th17 responses