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 b-glucosidase (glucocerebrosidase, GCase), the deficient enzyme in Gaucher disease. The synthesis of several new pyrrolidine analogues substituted at the nitrogen or a-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.

Human Acid β-Glucosidase Inhibition by Carbohydrate Derived Iminosugars: Towards New Pharmacological Chaperones for Gaucher Disease / Parmeggiani, Camilla; Catarzi, Serena; Matassini, Camilla; D’Adamio, Giampiero; Morrone, Amelia ; Goti, Andrea; Paoli, Paolo; Cardona, Francesca. - In: CHEMBIOCHEM. - ISSN 1439-4227. - STAMPA. - 16:(2015), pp. 2054-2064. [10.1002/cbic.201500292]

Human Acid β-Glucosidase Inhibition by Carbohydrate Derived Iminosugars: Towards New Pharmacological Chaperones for Gaucher Disease

PARMEGGIANI, CAMILLA;CATARZI, SERENA;MATASSINI, CAMILLA;D'ADAMIO, GIAMPIERO;MORRONE, AMELIA;GOTI, ANDREA;PAOLI, PAOLO;CARDONA, FRANCESCA
2015

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 b-glucosidase (glucocerebrosidase, GCase), the deficient enzyme in Gaucher disease. The synthesis of several new pyrrolidine analogues substituted at the nitrogen or a-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.
2015
16
2054
2064
Parmeggiani, Camilla; Catarzi, Serena; Matassini, Camilla; D’Adamio, Giampiero; Morrone, Amelia ; Goti, Andrea; Paoli, Paolo; Cardona, Francesca...espandi
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1010849
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