Journal
CHEMBIOCHEM
Volume 16, Issue 14, Pages 2054-2064Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.201500292
Keywords
Gaucher disease; GCase inhibition; iminosugars; natural products; synthesis
Funding
- Italian Ministry of Health and Regione Toscana [Ricerca Finalizzata-2011-02347694]
- MIUR Italy [2010L9SH3K 006]
- Ente Cassa di Risparmio di Firenze [2013/0366]
- Associazione Italiana Mucopolisaccaridosi e malattie affini (AIMPS)
- Associazione Malattie Metaboliche Congenite Ereditarie (AMMEC)
- Cell Line and DNA Biobank from Patients Affected by Genetic Diseases (G. Gaslini Institute)-Telethon Network of Genetic Biobanks [GTB07001]
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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 beta-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.
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