Ligand‐Controlled Stereoselective Synthesis and Biological Activity of 2‐Exomethylene Pseudo‐glycoconjugates: Discovery of Mincle‐Selective Ligands

Abstract

Glycoconjugate analogues in which the sp 3 -hybridized C2 position of the carbohydrate structure (normally bearing a hydroxy group) is converted into a compact sp 2 -hybridized exomethylene group are expected to have unique biological activities. We established ligand-controlled Tsuji-Trost-type glycosylation methodology to directly prepare a variety of these 2-exomethylene pseudo-glycoconjugates, including glucosylceramide analogues, in an α-or β-selective manner. Glucocerebrosidase GBA1 cleaves these synthetic pseudo-β-glucosylceramides similarly to native glucosylceramides. The pseudo-glucosylceramides exhibit selective ligand activity towards macrophage-inducible C-type lectin (Mincle), but unlike native glucosylceramides, are inactive towards CD1d.

Linkage-Editing Pseudo-Glycans: A Reductive α-Fluorovinyl-C-Glycosylation Strategy to Create Glycan Analogs with Altered Biological Activities

“…On the other hand, the F-atom-containing compounds 8 and 9 did not induce cytokine production, suggesting that they induce little or no iNKT cell activation through the TCR complex, even when presented on CD1d. To test this hypothesis, we performed iNKT cell activation in vitro using the NFAT-GFP reporter gene assay . While significant GFP expression by native α-GalCer was observed, indicating TCR-mediated iNKT cell activation (Figures D and S21), almost no GFP expression was observed in the presence of C-linked α-GalCer in this system.…”

“…To test this hypothesis, we performed iNKT cell activation in vitro using the NFAT-GFP reporter gene assay. 61 While significant GFP expression by native α-GalCer was observed, indicating TCR-mediated iNKT cell activation (Figures 5D and S21), almost no GFP expression was observed in the presence of Clinked α-GalCer in this system. Although CH 2 -linked 7 58,59 and (R)-CHF-linked 8 57 have been shown to be presented to CD1d, these results suggest that the activation of iNKT cells via the TCR complex by C-linked α-GalCer is weak.…”