Synthesis of α- and β-D-glucopyranosyl triazoles by CuAAC 'click chemistry': reactant tolerance, reaction rate, product structure and glucosidase inhibitory properties

Cu(I)-catalysed azide alkyne 1,3-dipolar cycloaddition (CuAAC) 'click chemistry' was used to assemble a library of 21 alpha-D- and beta-D-glucopyranosyl triazoles, which were assessed as potential glycosidase inhibitors. In the course of this work, different reactivities of isomeric alpha- and beta-glucopyranosyl azides under CuAAC conditions were noted. This difference was further investigated using competition reactions and rationalised on the basis of X-ray crystallographic data, which revealed significant differences in bond lengths within the azido groups of the alpha- and beta-anomers. Structural studies also revealed a preference for perpendicular orientation of the sugar and triazole rings in both the alpha- and beta-glucosyl triazoles in the solid state. The triazole library was assayed for inhibition of sweet almond beta-glucosidase (GH1) and yeast alpha-glucosidase (GH13), which led to the identification of a set of glucosidase inhibitors effective in the 100 mu M range. The preference for inhibition of one enzyme over the other proved to be dependent on the anomeric configuration of the inhibitor, as expected. (C) 2010 Elsevier Ltd. All rights reserved.