title: Galacto-configured aminocyclitol phytoceramides are potent in vivo invariant natural killer T cell stimulators.
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.
authors: Research Unit on BioActive Molecules (RUBAM), Departament de Química Biomèdica, Institut de Química Avançada de Catalunya (IQAC-CSIC), Jordi Girona 18-26, 08034 Barcelona, Spain.
authors: Youssef
authors: Y
authors: Harrak
authors: Carolina M
authors: CM
authors: Barra
authors: Antonio
authors: A
authors: Delgado
authors: A Raúl
authors: AR
authors: Castaño
authors: Amadeu
authors: A
authors: Llebaria
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D054812:Cyclitols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005699:Galactosylceramides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008968:Molecular Conformation; D055611:Natural Killer T-Cells / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D054812:Cyclitols; D005699:Galactosylceramides; C493154:alpha-galactosylceramide