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

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• 作者：Yongju Kim ; Keunhee Oh ; Heebum Song ; Dong-Sup Lee ; Seung Bum Park
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：September 12, 2013
• 年：2013
• 卷：56
• 期：17
• 页码：7100-7109
• 全文大小：437K
• 年卷期：v.56,no.17(September 12, 2013)
• ISSN：1520-4804

文摘

We designed and synthesized seven 伪-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 5 induced greater polarization toward Th2 and greater secretion of the immunomodulatory cytokine, IL-4, over secretion of pro-inflammatory cytokines, IFN-纬 and IL-17. Treatment of a single dose of analogue 5 markedly ameliorated disease pathogenesis in an animal model of an inflammatory demyelinating disease of the central nervous system, compared to that of KRN7000 (1). Therefore, this new 伪-GalCer analogue 5 is a novel iNKT ligand that stimulates the selective secretion of anti-inflammatory cytokines and regulates autoimmune diseases by reducing Th1 and Th17 responses.