Synthesis and evaluation of an α-C-Galactosylceramide analogue that induces Th1-biased responses in human natural killer T cells

An alpha-galactosylceramide (alpha GalCer, 1) and its isosteric C-glycoside analogue (2) were found to possess promising immunostimulatory activity because of their ability to activate natural killer T (NKT) cells. We report the synthesis of compound 3, a truncated nonisosteric C-alpha GalCer analogue, that like 2 is not enzymatically labile at the glycosidic linkage, but has the anomeric carbon directly bonded to the C1 of the phytoceramide backbone. We compared the biological activity of the three ligands using an in vitro system with human dendritic cells as the antigen-presenting cells and human NKT cells as the responding cells. Although 3 was a less potent agonist for NKT cells than 1 and 2, it induced cytokine production with the highest IFN-gamma:IL-4 and IFN-gamma:IL-13 ratios. Therefore, our data suggest that the new mimetic of alpha GalCer might preferentially promote Th1-immune responses and serve as a potent adjuvant in the immunotherapy of cancer and infectious diseases.