Synthesis of C-5″ and C-6″-modified α-GalCer analogues as iNKT-cell agonists.

Synthesis of C-5″ and C-6″-modified α-GalCer analogues as iNKT-cell agonists.
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DOI:
10.1016/j.bmc.2015.04.068
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发表时间:
2015-07-01
影响因子:
3.5
通讯作者:
Van Calenbergh S
Van Calenbergh S
中科院分区:
医学3区
文献类型:
--
作者:
Guillaume J;Pauwels N;Aspeslagh S;Zajonc DM;Elewaut D;Van Calenbergh S

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α-半乳糖神经酰胺(α-GalCer)是一种典型的非变性自然杀伤T (iNKT)细胞合成配体。在MHC i类分子CD1d呈递后,这种糖脂刺激iNKT细胞分泌大量促炎Th1和抗炎Th2细胞因子。最近,我们发现选定的6个″修饰的α-GalCer类似物可能由于与CD1d形成额外的锚点或通过与iNKT细胞的t细胞受体建立额外的相互作用而产生明显的th1偏倚反应。在这里,我们报道了α-GalCer的6″- o -氨基甲酸酯和半乳糖酰胺类似物的实际合成以及它们作为iNKT细胞激动剂在小鼠中的评价。
Alpha-Galactosyl Ceramide (α-GalCer) is a prototypical synthetic ligand of invariant natural killer T (iNKT) cells. Upon presentation by the MHC class I-like molecule CD1d, this glycolipid stimulates iNKT cells to secrete a vast amount of both pro-inflammatory Th1 and anti-inflammatory Th2 cytokines. Recently, we discovered that selected 6″-modified α-GalCer analogues may produce markedly Th1-biased responses due to the formation of either an additional anchor with CD1d or by establishing extra interactions with the T-cell receptor of iNKT cells. Here, we report a practical synthesis towards 6″-O-carbamate and galacturonamide analogues of α-GalCer and their evaluation as iNKT cell agonists in mice.
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