Journal
MOLECULES
Volume 25, Issue 19, Pages -Publisher
MDPI
DOI: 10.3390/molecules25194526
Keywords
synthesis; azasugars; iminosugars; lithium acetylides; lysosomal enzyme inhibitors; lysosomal storage disorders (LSDs); lysosomal sphingolipidoses; Gaucher disease
Funding
- Cassa di Risparmio di Pistoia e Pescia (Bando Giovani@Ricerca scientifica 2017)
- Fondazione CR Firenze [2017.0734, 2018.0942]
- Fondazione CR Firenze
- Ministerio de Economia y Competitividad of Spain [CTQ2016-77270-R]
- AMMeC (Associazione Malattie Metaboliche Congenite, Italy)
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Pharmacological chaperones (PCs) are small compounds able to rescue the activity of mutated lysosomal enzymes when used at subinhibitory concentrations. Nitrogen-containing glycomimetics such as aza- or iminosugars are known to behave as PCs for lysosomal storage disorders (LSDs). As part of our research into lysosomal sphingolipidoses inhibitors and looking in particular for new beta-galactosidase inhibitors, we report the synthesis of a series of alkylated azasugars with a relative all-cis configuration at the hydroxy/amine-substituted stereocenters. The novel compounds were synthesized from a common carbohydrate-derived piperidinone intermediate 8, through reductive amination or alkylation of the derived alcohol. In addition, the reaction of ketone 8 with several lithium acetylides allowed the stereoselective synthesis of new azasugars alkylated at C-3. The activity of the new compounds towards lysosomal beta-galactosidase was negligible, showing that the presence of an alkyl chain in this position is detrimental to inhibitory activity. Interestingly, 9, 10, and 12 behave as good inhibitors of lysosomal beta-glucosidase (GCase) (IC50 = 12, 6.4, and 60 mu M, respectively). When tested on cell lines bearing the Gaucher mutation, they did not impart any enzyme rescue. However, altogether, the data included in this work give interesting hints for the design of novel inhibitors.
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