New synthetic seven-membered 1-azasugars displaying potent inhibition towards glycosidases and glucosylceramide transferase

Several members of a new family of seven-membered azasugars, which can be seen as 1-azasugar ring homologues, have been obtained by simple chemical transformations starting from a sugar-derived azidolactol. Unlike their piperidine counterparts, these molecules are chemically stable when they possess a hydroxy group at the pseudo-C-2 position. Biological assays with a range of carbohydrate-processing enzymes have revealed interesting potential for these compounds. A trihydroxymethyl-substituted azepane displayed strong competitive inhibition on almond β-glucosidase (Ki=2.5 μM) while a trihydroxylated carboxylic acid derivative proved to be a potent and selective L-fucosidase inhibitor (Ki=41 nM). N-Butylation of these seven-membered 1-azasugars generated derivatives with some activity towards the Gaucher’s disease-related glucosylceramide transferase (IC50 75 μM) that did not interact significantly with digestive glucosidases.