title: Stereodivergent synthesis of right- and left-handed iminoxylitol heterodimers and monomers. Study of their impact on β-glucocerebrosidase activity.
abstract: A library of dimers and heterodimers of both enantiomers of 2-O-alkylated iminoxylitol derivatives has been synthesised and evaluated on β-glucocerebrosidase (GCase), the enzyme responsible for Gaucher disease (GD). Although the objective was to target simultaneously the active site and a secondary binding site of the glucosidase, the (-)-2-iminoxylitol moiety seemed detrimental for imiglucerase inhibition and no significant enhancement was obtained in G202R, N370S and L444P fibroblasts. However, all compounds having at least one (+)-2-O-alkyl iminoxylitol are GCase inhibitors in the nano molar range and are significant GCase activity enhancers in G202R fibroblats, as confirmed by a decrease of glucosylceramide levels and by co-localization studies.
authors.affiliation: Laboratoire de Synthèse Organique et Molécules Bioactives (SYBIO), Université de Strasbourg/CNRS (UMR 7509), Ecole Européenne de Chimie, Polymères et Matériaux (ECPM), 25 rue Becquerel, 67087 Strasbourg, France. philippe.compain@unistra.fr annebod@unistra.fr.
authors.forename: Fabien
authors.initials: F
authors.lastname: Stauffert
authors.forename: Jenny
authors.initials: J
authors.lastname: Serra-Vinardell
authors.forename: Marta
authors.initials: M
authors.lastname: Gómez-Grau
authors.forename: Helen
authors.initials: H
authors.lastname: Michelakakis
authors.forename: Irene
authors.initials: I
authors.lastname: Mavridou
authors.forename: Daniel
authors.initials: D
authors.lastname: Grinberg
authors.forename: Lluïsa
authors.initials: L
authors.lastname: Vilageliu
authors.forename: Josefina
authors.initials: J
authors.lastname: Casas
authors.forename: Anne
authors.initials: A
authors.lastname: Bodlenner
authors.forename: Antonio
authors.initials: A
authors.lastname: Delgado
authors.forename: Philippe
authors.initials: P
authors.lastname: Compain
mesh_terms: D020134:Catalytic Domain; D060326:Chemistry Techniques, Synthetic; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D005776:Gaucher Disease / Q000201:enzymology; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D021381:Protein Transport; D013237:Stereoisomerism; D014993:Xylitol / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D005962:Glucosylceramidase; D014993:Xylitol