Stereoselective Synthesis and Immunogenic Activity of the C-Analogue of Sulfatide Emilia Modica, † Federica Compostella,* ,† Diego Colombo, † Laura Franchini, † Marco Cavallari, ‡ Lucia Mori, ‡ Gennaro De Libero, ‡ Luigi Panza, § and Fiamma Ronchetti † Dipartimento di Chimica, Biochimica e Biotecnologie per la Medicina, UniVersita ` di Milano, Via Saldini 50, 20133-Milano, Italy, Experimental Immunology, Department of Research, Basel UniVersity Hospital, Hebelstrasse 20, 4031-Basel, Switzerland, and Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, UniVersita ` del Piemonte Orientale, Via BoVio 6, 28100-NoVara, Italy federica.compostella@unimi.it Received May 4, 2006 ABSTRACT The C-sulfatide 1b was synthesized through a [2,3]-Wittig sigmatropic rearrangement and a Horner-Wadsworth-Emmons olefination as the key steps. The C-analogue 1b is less immunogenic than natural sulfatide 1a, but induces a preferential secretion of the proinflammatory cytokine IFN-γ. CD1 antigen-presenting molecules present different types of self and foreign lipid antigens to T lymphocytes which recognize the CD1-lipid complexes on the surface of antigen- presenting cells. 1 CD1-restricted T cells exert a wide range of effector functions. They secrete a large variety of cytokines upon T cell receptor (TCR) triggering, including IFN-γ and IL-4, and participate in both proinflammatory and anti- inflammatory immune responses. 2 The role of T cells reacting against self-glycosphingolipids in autoimmune diseases, such as in Multiple Sclerosis, has been clarified by both in vitro and ex vivo data. 3 Recent studies have demonstrated the importance in their immuno- genicity of both the lipid and the sugar structures. For example, modifications in the fatty acids of GM1 ganglioside or of phospholipids may profoundly hinder the response of specific T cells. 4 Also the structure of the sphingosine chain contributes to immunogenicity. These modifications have been associated with modifications in the structures of CD1- lipid complexes which interact with the TCR or with differences in the half-life of the immunogenic complexes. 5 Finally, the structure of the sugar moiety is also very important, mostly because the TCR establishes cognate interactions with parts of the hydrophilic moiety of glyco- lipids. Therefore, the position of the hydroxyl groups as well as the type of glycosidic bonds play critical roles in immunogenicity. Interestingly, modifications in the glyco- † Universita ` di Milano. ‡ Basel University Hospital. § Universita ` del Piemonte Orientale. (1) (a) De Libero, G.; Mori, L. Nat. ReV. Immunol. 2005, 5, 485-496. (b) Moody, D. B.; Zajonc, D. M.; Wilson, I. A. Nat. ReV. Immunol. 2005, 5, 387-399. (2) De Libero, G.; Donda, A.; Gober, H. J.; Manolova, V.; Mazorra, Z.; Shamshiev, A.; Mori, L. Neurochem. Res. 2002, 27, 675-685. (3) Shamshiev, A.; Donda, A.; Carena, I.; Mori, L.; Kappos, L.; De Libero, G. Eur. J. Immunol. 1999, 29, 1667-1675 (4) Shamshiev, A.; Donda, A.; Prigozy, T. I.; Mori, L.; Chigorno, V.; Benedict, C. A.; Kappos, L.; Sonnino, S.; Kronenberg, M.; De Libero, G. Immunity 2000, 13, 255-264. (5) (a) Miyamoto, K.; Miyake, S.; Yamamura, T. Nature 2001 413, 531- 534. (b) Ndonye, R M.; Izmirian, D. P.; Dunn, M. F.; Yu, K. O. A.; Porcelli, S. A.; Khurana, A.; Kronenberg, M.; Richardson, S. K.; Howell, A. R. J. Org. Chem. 2005, 70, 10260-10270 ORGANIC LETTERS 2006 Vol. 8, No. 15 3255-3258 10.1021/ol061100y CCC: $33.50 © 2006 American Chemical Society Published on Web 06/28/2006