title: Human Acid β-Glucosidase Inhibition by Carbohydrate Derived Iminosugars: Towards New Pharmacological Chaperones for Gaucher Disease.
abstract: A collection of carbohydrate-derived iminosugars belonging to three structurally diversified sub-classes (polyhydroxylated pyrrolidines, piperidines, and pyrrolizidines) was evaluated for inhibition of human acid β-glucosidase (glucocerebrosidase, GCase), the deficient enzyme in Gaucher disease. The synthesis of several new pyrrolidine analogues substituted at the nitrogen or α-carbon atom with alkyl chains of different lengths suggested an interpretation of the inhibition data and led to the discovery of two new GCase inhibitors at sub-micromolar concentration. In the piperidine iminosugar series, two N-alkylated derivatives were found to rescue the residual GCase activity in N370S/RecNcil mutated human fibroblasts (among which one up to 1.5-fold). This study provides the starting point for the identification of new compounds in the treatment of Gaucher disease.
authors.affiliation: Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 3-13, 50019, Sesto Fiorentino, Italy.|CNR-INO, U.O.S. Sesto Fiorentino and LENS, Via Nello Carrara 1, 50019, Sesto Fiorentino, Italy.
authors.forename: Camilla
authors.initials: C
authors.lastname: Parmeggiani
authors.affiliation: Paediatric Neurology Unit and Laboratories, Neuroscience Department, Meyer Children's Hospital, Department of Neurosciences, Pharmacology and Child Health, University of Florence, Viale Pieraccini n. 24, 50139, Firenze, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Catarzi
authors.affiliation: Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 3-13, 50019, Sesto Fiorentino, Italy.
authors.forename: Camilla
authors.initials: C
authors.lastname: Matassini
authors.affiliation: Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 3-13, 50019, Sesto Fiorentino, Italy.
authors.forename: Giampiero
authors.initials: G
authors.lastname: D'Adamio
authors.affiliation: Paediatric Neurology Unit and Laboratories, Neuroscience Department, Meyer Children's Hospital, Department of Neurosciences, Pharmacology and Child Health, University of Florence, Viale Pieraccini n. 24, 50139, Firenze, Italy. amelia.morrone@unifi.it, a.morrone@meyer.it.
authors.forename: Amelia
authors.initials: A
authors.lastname: Morrone
authors.affiliation: Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 3-13, 50019, Sesto Fiorentino, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Goti
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134, Florence, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Paoli
authors.affiliation: Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 3-13, 50019, Sesto Fiorentino, Italy. francesca.cardona@unifi.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cardona
mesh_terms: D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005776:Gaucher Disease / Q000188:drug therapy / Q000201:enzymology*; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D050111:Imino Sugars / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D050111:Imino Sugars; D005962:Glucosylceramidase
keywords: GCase inhibition; Gaucher disease; iminosugars; natural products; synthesis