title: New synthetic seven-membered 1-azasugars displaying potent inhibition towards glycosidases and glucosylceramide transferase.
abstract: 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 beta-glucosidase (K(i)=2.5 microM) while a trihydroxylated carboxylic acid derivative proved to be a potent and selective L-fucosidase inhibitor (K(i)=41 nM). N-Butylation of these seven-membered 1-azasugars generated derivatives with some activity towards the Gaucher's disease-related glucosylceramide transferase (IC(50) 75 microM) that did not interact significantly with digestive glucosidases.
authors.affiliation: UMR 7611, Laboratoire de Synthèse Organique, Institut de Chimie Moléculaire (FR 2769), Université Pierre et Marie Curie-Paris 6, 75005 Paris, France.
authors.forename: Hongqing
authors.initials: H
authors.lastname: Li
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.forename: Yongmin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Sylvain
authors.initials: S
authors.lastname: Favre
authors.forename: Claudia
authors.initials: C
authors.lastname: Bello
authors.forename: Pierre
authors.initials: P
authors.lastname: Vogel
authors.forename: Terry D
authors.initials: TD
authors.lastname: Butters
authors.forename: Nikos G
authors.initials: NG
authors.lastname: Oikonomakos
authors.forename: Jérôme
authors.initials: J
authors.lastname: Marrot
authors.forename: Yves
authors.initials: Y
authors.lastname: Blériot
mesh_terms: D001372:Aza Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D001381:Azepines / Q000138:chemical synthesis* / Q000494:pharmacology; D001681:Biological Assay; D002241:Carbohydrates / Q000138:chemical synthesis* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D005776:Gaucher Disease / Q000188:drug therapy / Q000473:pathology; D005963:Glucosylceramides / Q000037:antagonists & inhibitors*; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors*; D016695:Glycosyltransferases / Q000037:antagonists & inhibitors*
chemical_list: D001372:Aza Compounds; D001381:Azepines; D002241:Carbohydrates; D004791:Enzyme Inhibitors; D005963:Glucosylceramides; D016695:Glycosyltransferases; D006026:Glycoside Hydrolases