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Please use this identifier to cite or link to this item: http://hdl.handle.net/10261/48566
Title: Galacto-Configured Aminocyclitol Phytoceramides Are Potent in Vivo Invariant Natural Killer T Cell Stimulators
Authors: Harrak Serifi, Youssef; Barra, Carolina M.; Delgado, Antonio; Castaño, A. Raúl; Llebaria, Amadeu
Issue Date: 2011
Publisher: American Chemical Society
Citation: Journal of the American Chemical Society
Abstract: A new class of α-galactosylceramide (αGC) nonglycosidic analogues bearing galacto-configured aminocyclitols as sugar surrogates have been obtained. The aminocyclohexane having a hydroxyl substitution pattern similar to an α-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 αGC. This compound stimulates the release of Interferon-γ (IFNγ) and Interleukin-4 (IL-4) in iNKT cell culture but with lower potency than αGC. 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-γ indicative of a potent Th1 cytokine profile. Overall, these data confirm the agonist activity of αGC lipid analogues having charged amino-substituted polar heads and their capacity to modulate the response arising from iNKT cell activation in vivo.
Publisher version (URL): http://dx.doi.org/10.1021/ja202610x
URI: http://hdl.handle.net/10261/48566
DOI: 10.1021/ja202610x
ISSN: 0002-7863
E-ISSN: 1520-5126
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