Epóxidos y aziridinas de ciclohexano relacionados estructuralmente con la galactosa como inhibidores selectivos de galactosidasas

La presente invención se refiere a una familia de epóxidos y aziridinas derivadas de ciclohexano que poseen una similitud estructural con la galactosa y presentan propiedades como inhibidores de galactosidasas. Además la presente invención también se refiere al uso de estos compuestos como herramienta biotecnológica, como reactivo de biología molecular, así como, para la preparación de un medicamento para el tratamiento de enfermedades asociadas a la glicosilación de lípidos y proteínas.Peer reviewedConsejo Superior de Investigaciones Científicas (España)A1 Solicitud de patente con informe sobre el estado de la técnic

Compuestos aminociclitoles, procedimiento de obtención y usos

Compuestos aminociclitoles, procedimiento de obtención y usos. Compuestos aminociclitoles y sus usos como composiciones farmacéuticas para el tratamiento de enfermedades asociadas con alteraciones en las células iNKT, más concretamente a enfermedades autoinmunes, cáncer, infecciones causadas por microorganismos patógenos o enfermedades inflamatorias. Además, la invención se refiere al procedimiento de obtención de dichos compuestos.Peer reviewedConsejo Superior de Investigaciones Científicas (España), Universidad Autónoma de Barcelona, Universidad de BarcelonaA1 Solicitud de patente con informe sobre el estado de la técnic

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

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.This work was supported by MICINN (Project CTQ2008–01426/BQU), Fondos Feder (EU), Generalitat de Catalunya (2005SGR01063), UAB (PRP2007–06), and CSIC (200480E561). The authors thank E. Dalmau for HRMS analysis and Dr, M. Egido-Gabas and Dr. Amaya Castro for analytical support. Y.H. thanks MICINN for a Juan de la Cierva fellowship.Peer reviewe

NKT TCR Recognition of CD1d-α-C-Galactosylceramide

NKT cells respond to a variety of CD1d-restricted glycolipid Ags that are structurally related to the prototypic Ag α-galactosylceramide (α-GalCer). A modified analog of α-GalCer with a carbon-based glycosidic linkage (α-C-GalCer) has generated great interest because of its apparent ability to promote prolonged, Th1-biased immune responses. In this study, we report the activation of spleen NKT cells to α-C-GalCer, and related C-glycoside ligands, is weaker than that of α-GalCer. Furthermore, the Vβ8.2 and Vβ7 NKT TCR affinity for CD1d–α-C-GalCer, and some related analogs, is ∼10-fold lower than that for the NKT TCR–CD1d–α-GalCer interaction. Nevertheless, the crystal structure of the Vβ8.2 NKT TCR–CD1d–α-C-GalCer complex is similar to that of the corresponding NKT TCR–CD1d–α-GalCer complex, although subtle differences at the interface provide a basis for understanding the lower affinity of the NKT TCR–CD1d–α-C-GalCer interaction. Our findings support the concept that for CD1d-restricted NKT cells, altered glycolipid ligands can promote markedly different responses while adopting similar TCR-docking topologies.We thank the synchrotron staff at the MX2 beamline of the Australian synchrotron for assistance with data collection and David Taylor and the animal house staff at the University of Melbourne, Department of Microbiology and Immunology, for animal husbandry assistance. We also thank the National Institutes of Health tetramer facility for providing us with a-C-GalCer and Maria Sandoval for technical assistance.Peer reviewe