Synthesis of alpha- and beta-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 microM range. The preference for inhibition of one enzyme over the other proved to be dependent on the anomeric configuration of the inhibitor, as expected.
Dedola
Simone
S
Department of Biological Chemistry, John Innes Centre, Colney Lane, Norwich, UK.
Hughes
David L
DL
Nepogodiev
Sergey A
SA
Rejzek
Martin
M
Field
Robert A
RA
D000480:Alkynes / Q000737:chemistry*; D001386:Azides / Q000737:chemistry*; D002384:Catalysis; D003300:Copper / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005959:Glucosidases / Q000037:antagonists & inhibitors*; D007700:Kinetics; D027861:Prunus / Q000201:enzymology; D013237:Stereoisomerism; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D000480:Alkynes; D001386:Azides; D004791:Enzyme Inhibitors; D014230:Triazoles; D003300:Copper; D005959:Glucosidases