Synthesis and biological activity of alpha-glucosyl C24:0 and C20:2 ceramides.
Bottom Line: Alpha-glucosyl ceramides 4 and 5 have been synthesised and evaluated for their ability to stimulate the activation and expansion of human iNKT cells.The key challenge in the synthesis of both target molecules was the stereoselective synthesis of the alpha-glycosidic linkage.Of the methods examined, glycosylation using per-TMS-protected glucosyl iodide 16 was completely alpha-selective and provided gram quantities of amine 11, from which alpha-glucosyl ceramides 4 and 5 were obtained by N-acylation. alpha-GlcCer 4, containing a C24 saturated acyl chain, stimulated a marked proliferation and expansion of human circulating iNKT cells in short-term cultures. alpha-GlcCer 5, which contains a C20 11,14-cis-diene acyl chain (C20:2), induced extremely similar levels of iNKT cell activation and expansion.
Affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham, UK.Show MeSH
Mentions: Although extensive studies have examined the impact on the iNKT cell-stimulating activities of modifications to the fatty acyl and sphingosine structures of α-GalCer, there has been less analysis of the effects of structural modifications of the carbohydrate head group.17 Subtle changes in this part of the glycolipid are likely to have significant effects on iNKT cell recognition since the monosaccharide group is exposed and makes direct contacts with the TCR in complexes formed by the binding of α-GalCer to CD1d.18 To this end, we now report the synthesis and preliminary biological activity of α-glucosyl ceramide analogues 4 and 5 (Fig. 2).
Affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham, UK.