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Closed Access item Galacto-Configured Aminocyclitol Phytoceramides Are Potent in Vivo Invariant Natural Killer T Cell Stimulators
|Authors:||Harrak Serifi, Youssef|
Barra, Carolina M.
Castaño, A. Raúl
Llebaria Soldevilla, Amadeu
|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|
|Appears in Collections:||(IQAC) Artículos|
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