6′-Derivatised α-GalCer Analogues Capable of Inducing Strong CD1d-Mediated Th1-Biased NKT Cell Responses in Mice

alpha-Galactosyl ceramide (alpha-GalCer, also known as KRN 7000) is known as the prototypical antigen for invariant natural killer T (NKT) Celts. Stimulation of NKT Celts by Old-mediated alpha-GalCer presentation leads to rapid release of Th1 and Th2 cytokines. Since Th1 and Th2 cytokines antagonize each other's effects, alpha-GalCer analogues that induce a biased Th1/Th2 response are highly awaited. With the exception of a C-glycoside (alpha-C-GalCer), most of the known alpha-GalCer analogues able to induce polarized cytokine responses are characterized by modifications of the phytosphingosine or fatty acyl chains, expected to alter the affinity for Old. Herein we describe the synthesis of 6'-modified alpha-GalCer analogues with an intact phytoceramide moiety that are capable to skew the cytokine release profile to Th1, white maintaining strong antigenic activity. These analogues are characterized by the presence of an aromatic moiety that is connected via an amide or an urea linkage to C'-6 of the galactopyranose ring.