NKT cell is a potent producer of immunoregulatory cytokines. T cell receptor of NKT cell recognizes CD1d protein-α-galactosylceramide complex, and activated NKT cell can produce the both Th1 (immunostimulant) and Th2 (immunosuppressant)-types cytokines. KRN7000 (2), developed by Kirin Brewery Co. Ltd., is a derivative of natural α-galactosylceramide, agerasphins (main component is agelasphin-9b, 1). KRN7000 is a strong stimulant to NKT cells. However, it induces both Th1 and Th2-type cytokines production of NKT cell by single stimulation. The analogue OCH (3), possessing shorter alkyl chains as developed by Yamamura et al., induces predominant production of interleukin (IL)-4, a key cytokine of Th2 type, over Th1 type cytokines. The total amount of IL-4, produced by NKT cells by stimulation with OCH, however, was less than that in the case of 2. For improvement of this problem, we developed two kinds of new galactosylceramides. One of them is those possessing a ring structure on the sphingosine chain. This analogue was synthesized from the known epoxide 6. The selective reductive-epoxide opening reaction to 6 afforded alcohol 7 or 12. The four-membered ring part was constructed from alcohol 7, whereas alcohol 12 was converted to the five-membered ring part. The resulting products were converted to the corresponding galactosylceramides respectively. Another kind of the analogues (21) were those possessing sulfonamide chain instead of the acyl chain. Those analogues could be synthesized easily from the commercially available phytosphingosine (17). Both analogues could make complexes with CD1d, and induce NKT cells to produce Th1 type cytokine predominantly.
