Galacto-Configured Aminocyclitol Phytoceramides Are Potent in Vivo Invariant Natural Killer T Cell Stimulators
Galacto-Configured Aminocyclitol Phytoceramides Are Potent in Vivo Invariant Natural Killer T Cell Stimulators
复制标题
DOI：
10.1021/ja202610x
复制
发表时间：
2011-08-10
影响因子：
15
通讯作者：
Llebaria, Amadeu
中科院分区：
文献类型：
--
作者：
Harrak, Youssef;Barra, Carolina M.;Llebaria, Amadeu
已经获得了一类新的α-半乳糖基神经酰胺（α GC）非糖苷类似物，其带有半乳糖构型的氨基环醇作为糖替代物。具有类似于α-半乳糖苷的羟基取代模式的氨基环己烷通过涉及Evans羟醛反应和用Grubbs催化剂的闭环复分解以得到关键中间体环己烯的序列有效地获得，所述关键中间体环己烯已转化为半乳糖-氨基环己烷，所述半乳糖-氨基环己烷通过仲胺连接到具有蜡基N-酰基的植物神经酰胺脂质。自然杀伤T（NKT）细胞测定已经鉴定出活性化合物HS 161，已经发现其以类似的方式促进NKT细胞体外扩增，但比α GC更弱。该化合物刺激iNKT细胞培养物中干扰素-γ（IFN γ）和白细胞介素-4（IL-4）的释放，但效力低于α GC。在流式细胞术实验中证实了该化合物对不变自然杀伤T（iNKT）细胞的激活作用。值得注意的是，当在小鼠中测试时，HS 161选择性地诱导非常强的IFN-γ产生，这表明有效的Th 1细胞因子谱。总之，这些数据证实了具有带电荷的氨基取代的极性头部的α GC脂质类似物的激动剂活性及其调节体内iNKT细胞活化引起的应答的能力。
A new class of a-galactosylceramide (alpha GC) nonglycosidic analogues bearing galacto-configured aminocyclitols as sugar surrogates have been obtained. The aminocyclohexane having a hydroxyl substitution pattern similar to an a-galactoside is efficiently obtained by a sequence involving Evans aldol reaction and ring-closing metathesis with a Grubbs catalyst to give a key intermediate cyclohexene, which has been converted in galacto-aminocyclohexanes that are linked through a secondary amine to a phytoceramide lipid having a cerotyl N-acyl group. Natural Killer T (NKT) cellular assays have resulted in the identification of an active compound, HS161, which has been found to promote NKT cell expansion in vitro in a similar fashion but more weakly than alpha GC. This compound stimulates the release of Interferon-gamma (IFN gamma) and Interleukin-4 (IL-4) in iNKT cell culture but with lower potency than alpha GC. The activation of Invariant Natural Killer T (iNKT) cells by this compound has been confirmed in flow cytometry experiments. Remarkably, when tested in mice, HS161 selectively induces a very strong production of IFN-gamma indicative of a potent Th1 cytokine profile. Overall, these data confirm the agonist activity of alpha GC lipid analogues having charged amino-substituted polar heads and their capacity to modulate the response arising from iNKT cell activation in vivo.