Intramolecular Nitrogen Delivery for the Synthesis of C-Glycosphingolipids. Application to the C-Glycoside of the Immunostimulant KRN7000

The key reaction in this approach to C-glycosphingolipids is the stereoselective iodocyclization of a sugar-linked homoallylic carbonimidothioate. E and Z reaction substrates were assembled in a convergent fashion via an alkene metathesis strategy and exhibited the same alkene facial selectivity in the iodocyclization irrespective of alkene geometry, although the E alkene was found to be less reactive

Abrogation of Endogenous Glycolipid Antigen Presentation on Myelin-Laden Macrophages by D-Sphingosine Ameliorates the Pathogenesis of Experimental Autoimmune Encephalomyelitis

Background: Although myelin is composed of mostly lipids, the pathological role of myelin lipids in demyelinating diseases remains elusive. The principal lipid of the myelin sheath is β-galactosylceramide (β-Galcer). Its α-anomer (α-Galcer) has been demonstrated to be antigenically presented by macrophages via CD1d, a MHC class I-like molecule. Myelin, which is mostly composed of β-Galcer, has been long considered as an immunologically-inert neuron insulator, because the antigen-binding cleft of CD1d is highly α-form-restricted.Results: Here, we report that CD1d-mediated antigenic presentation of myelin-derived galactosylceramide (Mye-GalCer) by macrophages contributed significantly to the progression of experimental autoimmune encephalomyelitis (EAE). Surprisingly, this presentation was recognizable by α-Galcer:CD1d-specific antibody (clone L363), but incapable of triggering expansion of iNKT cells and production of iNKT signature cytokines (IFNγ and IL-4). Likewise, a synthesized analog of Mye-Galcer, fluorinated α-C-GalCer (AA2), while being efficiently presented via CD1d on macrophages, failed to stimulate production of IFNγ and IL-4. However, AA2 significantly exacerbated EAE progression. Further analyses revealed that the antigenic presentations of both Mye-GalCer and its analog (AA2) in α-form via CD1d promoted IL-17 production from T cells, leading to elevated levels of IL-17 in EAE spinal cords and sera. The IL-17 neutralizing antibody significantly reduced the severity of EAE symptoms in AA2-treated mice. Furthermore, D-sphingosine, a lipid possessing the same hydrophobic base as ceramide but without a carbohydrate residue, efficiently blocked this glycolipid antigen presentation both in vitro and in spinal cords of EAE mice, and significantly decreased IL-17 and ameliorated the pathological symptoms.Conclusion: Our findings reveal a novel pathway from the presentation of Mye-GalCer to IL-17 production, and highlight the promising therapeutic potential of D-sphingosine for the human disorder of multiple sclerosis

Intramolecular Nitrogen Delivery for the Synthesis of C‑Glycosphingolipids. Application to the C‑Glycoside of the Immunostimulant KRN7000

The key reaction in this approach to C-glycosphingolipids is the stereoselective iodocyclization of a sugar-linked homoallylic carbonimidothioate. <i>E</i> and <i>Z</i> reaction substrates were assembled in a convergent fashion via an alkene metathesis strategy and exhibited the same alkene facial selectivity in the iodocyclization irrespective of alkene geometry, although the <i>E</i> alkene was found to be less reactive

The Crotylation Way to Glycosphingolipids: Synthesis of Analogues of KRN7000

A synthesis of glycosphingolipids that centers on the reaction of <i>O</i>- and <i>C</i>-glycosyl crotylstannanes and relatively simple lipid aldehydes is described. The modularity of this strategy and versatility of the crotylation products make this an attractive approach to diverse, highly substituted libraries. The methodology is applied to analogues of the potent imunostimulatory glycolipid KRN7000, including O-, methylene-, and fluoromethine-linked isosteres with diastereomeric ceramide segments and 2-amido substitutes