Synthesis and Biological Evaluation of α‑Galactosylceramide Analogues with Heteroaromatic Rings and Varying Positions of a Phenyl Group in the Sphingosine Backbone

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