Galacto-Configured Aminocyclitol Phytoceramides Are Potent in Vivo Invariant Natural Killer T Cell Stimulators

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• 作者：Youssef Harrak ; Carolina M. Barra ; Antonio Delgado ; A. Ra煤l Casta帽o ; Amadeu Llebaria
• 刊名：Journal of the American Chemical Society
• 出版年：2011
• 出版时间：August 10, 2011
• 年：2011
• 卷：133
• 期：31
• 页码：12079-12084
• 全文大小：882K
• 年卷期：v.133,no.31(August 10, 2011)
• ISSN：1520-5126

文摘

A new class of 伪-galactosylceramide (伪GC) nonglycosidic analogues bearing galacto-configured aminocyclitols as sugar surrogates have been obtained. The aminocyclohexane having a hydroxyl substitution pattern similar to an 伪-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 伪GC. This compound stimulates the release of Interferon-纬 (IFN纬) and Interleukin-4 (IL-4) in iNKT cell culture but with lower potency than 伪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-纬 indicative of a potent Th1 cytokine profile. Overall, these data confirm the agonist activity of 伪GC lipid analogues having charged amino-substituted polar heads and their capacity to modulate the response arising from iNKT cell activation in vivo.