title: N-Alkyl-, 1-C-Alkyl-, and 5-C-Alkyl-1,5-dideoxy-1,5-imino-(L)-ribitols as Galactosidase Inhibitors.
abstract: A series of 1,5-dideoxy-1,5-imino-(l)-ribitol (DIR) derivatives carrying alkyl or functionalized alkyl groups were prepared and investigated as glycosidase inhibitors. These compounds were designed as simplified 4-epi-isofagomine (4-epi-IFG) mimics and were expected to behave as selective inhibitors of β-galactosidases. All compounds were indeed found to be highly selective for β-galactosidases versus α-glycosidases, as they generally did not inhibit coffee bean α-galactosidase or other α-glycosidases. Some compounds were also found to be inhibitors of almond β-glucosidase. The N-alkyl DIR derivatives were only modest inhibitors of bovine β-galactosidase, with IC50 values in the 30-700 μM range. Likewise, imino-L-ribitol substituted at the C1 position was found to be a weak inhibitor of this enzyme. In contrast, alkyl substitution at C5 resulted in enhanced β-galactosidase inhibitory activity by a factor of up to 1000, with at least six carbon atoms in the alkyl substituent. Remarkably, the 'pseudo-anomeric' configuration in this series does not appear to play a role. Human lysosomal β-galactosidase from leukocyte lysate was, however, poorly inhibited by all iminoribitol derivatives tested (IC50 values in the 100 μM range), while 4-epi-IFG was a good inhibitor of this enzyme. Two compounds were evaluated as pharmacological chaperones for a GM1-gangliosidosis cell line (R301Q mutation) and were found to enhance the mutant enzyme activity by factors up to 2.7-fold.
authors.affiliation: Institut de Chimie Organique et Analytique (ICOA), UMR 7311, Université d'Orléans, Centre National de la Recherche Scientifique (CNRS), Rue de Chartres, 45067, Orléans, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Front
authors.affiliation: Institut de Chimie Organique et Analytique (ICOA), UMR 7311, Université d'Orléans, Centre National de la Recherche Scientifique (CNRS), Rue de Chartres, 45067, Orléans, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Gallienne
authors.affiliation: Dorphan SA, EPFL Innovation Park, 1015, Lausanne, Switzerland.
authors.forename: Julie
authors.initials: J
authors.lastname: Charollais-Thoenig
authors.affiliation: Dorphan SA, EPFL Innovation Park, 1015, Lausanne, Switzerland.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Demotz
authors.affiliation: Institut de Chimie Organique et Analytique (ICOA), UMR 7311, Université d'Orléans, Centre National de la Recherche Scientifique (CNRS), Rue de Chartres, 45067, Orléans, France. Olivier.Martin@univ-orleans.fr.
authors.forename: Olivier R
authors.initials: OR
authors.lastname: Martin
mesh_terms: D000818:Animals; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D005696:Galactosidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000201:enzymology; D008968:Molecular Conformation; D012255:Ribitol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D012255:Ribitol; D005696:Galactosidases
keywords: GM1-gangliosidosis; carbohydrates; drug design; galactosidase inhibitors; iminosugars; pharmacological chaperones