Abstract
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 β-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 β-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 β-glucosidase (GCase) (IC50 = 12, 6.4, and 60 µM, 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.
Highlights
Lysosomal storage disorders (LSDs) are a group of more than 70 inherited orphan diseases caused by specific mutations in genes encoding lysosomal enzymes and characterized by progressive accumulation of substrates within the lysosomes, leading to organ dysfunctions [1,2,3,4].Defective activity of lysosomal β-galactosidase (β-Gal), which is responsible for the hydrolytic removal of a terminal β-galactose residue from several glycoconjugates, leads to two different typesMolecules 2020, 25, 4526; doi:10.3390/molecules25194526 www.mdpi.com/journal/molecules of rare lysosomal storage disorders (LSDs), the sphingolipidosis GM1-gangliosidosis and the mucopolysaccharidosis IVB (MPSIVB, known as Morquio disease type B) [5,6]
“all-cis” alcohol followed by Williamson reaction to afford the ether 9; (ii) reductive amination of 8 with dodecyl amine provided the new amino azasugar 10; and (iii) addition of organolithium derivatives followed by proper manipulation allowed access to diversely C-3 functionalized compounds 11–15
8, precursor of allamino the newazasugar compounds, synthesized as reported from aldehyde 16, dodecyl amineKetone provided the new 10;was and (iii) addition of organolithium derivatives derived in turn from inexpensive D-mannose in four steps with a high overall yield (85%)
Summary
Lysosomal storage disorders (LSDs) are a group of more than 70 inherited orphan diseases caused by specific mutations in genes encoding lysosomal enzymes and characterized by progressive accumulation of substrates within the lysosomes, leading to organ dysfunctions [1,2,3,4].Defective activity of lysosomal β-galactosidase (β-Gal), which is responsible for the hydrolytic removal of a terminal β-galactose residue from several glycoconjugates, leads to two different typesMolecules 2020, 25, 4526; doi:10.3390/molecules25194526 www.mdpi.com/journal/molecules of rare LSDs, the sphingolipidosis GM1-gangliosidosis and the mucopolysaccharidosis IVB (MPSIVB, known as Morquio disease type B) [5,6]. Lysosomal storage disorders (LSDs) are a group of more than 70 inherited orphan diseases caused by specific mutations in genes encoding lysosomal enzymes and characterized by progressive accumulation of substrates within the lysosomes, leading to organ dysfunctions [1,2,3,4]. Molecules 2020, 25, 4526; doi:10.3390/molecules25194526 www.mdpi.com/journal/molecules of rare LSDs, the sphingolipidosis GM1-gangliosidosis and the mucopolysaccharidosis IVB Typical substrates of β-Gal are GM1-gangliosides, glycoproteins, oligosaccharides, and glycosaminoglycan keratan sulfate, which accumulate inside the lysosomes due to the malfunctioning enzyme, which usually presents a mutation in its natural amino acid sequence. Pharmacological chaperone therapy (PCT) is emerging as a promising therapeutic approach for the treatment of LSDs, especially for those that cannot be treated with enzyme replacement therapy of rare PCT.
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