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

다국어 초록 (Multilingual Abstract)

<P>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.</P><P><B>Graphic Abstract</B>
<IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jmcmar/2013/jmcmar.2013.56.issue-17/jm400949h/production/images/medium/jm-2013-00949h_0007.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/jm400949h'>ACS Electronic Supporting Info</A></P>