Synthesis and Biological Evaluation of α-Galactosylceramide Analogues with Heteroaromatic Rings and Varying Positions of a Phenyl Group in the Sphingosine Backbone
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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DOI：
10.1021/jm400949h
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发表时间：
2013-09-12
影响因子：
7.3
通讯作者：
Park, Seung Bum
中科院分区：
文献类型：
--
作者：
Kim, Yongju;Oh, Keunhee;Park, Seung Bum
我们设计并合成了七种具有吡唑部分和鞘氨醇骨架中不同位置苯基的α-GalCer类似物，以极化细胞因子分泌。在体外和体内生物学评价的基础上，我们发现类似物5诱导更大的向Th 2极化和免疫调节细胞因子IL-4的更大分泌，促炎细胞因子IFN-γ和IL-17的过度分泌。与KRN 7000相比，单剂量类似物5的治疗显著改善了中枢神经系统炎性脱髓鞘疾病动物模型中的疾病发病机制（1）。因此，这种新的α-GalCer类似物5是一种新型的iNKT配体，其刺激抗炎细胞因子的选择性分泌，并通过减少Th 1和Th 17应答来调节自身免疫性疾病。
We designed and synthesized seven alpha-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-gamma 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 alpha-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.