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

Abstract

The acetal ( O -glycoside) bonds of glycans and glycoconjugates are chemically and biologically vulnerable, and therefore C -glycosides are of interest as more stable analogs. We hypothesized that, if the O -glycoside linkage plays a vital role in glycan function, the biological activities of C -glycoside analogs would vary depending on their substituents. Based on this idea, we adopted a “linkage-editing strategy” for the creation of glycan analogs (pseudo-glycans). We designed three types of pseudo-glycans with CH 2 and CHF linkages, which resemble the O -glycoside linkage in terms of bond lengths, angles, and bulkiness, and synthesized them efficiently by means of fluorovinyl C -glycosylation and selective hydrogenation reactions. Application of this strategy to isomaltose (IM), an inducer of amylase expression, and α-GalCer, which activates iNKT cells, resulted in the discovery of CH 2 -IM, which shows increased amylase production ability, and CHF-α-GalCer, which shows activity opposite that of native α-GalCer, serving as an antagonist of iNKT cells.