Synthesis of “<i>All-Cis”</i> Trihydroxypiperidines from a Carbohydrate-Derived Ketone: Hints for the Design of New β-Gal and GCase Inhibitors
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 res...
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MDPI AG
2020-10-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/19/4526 |
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| author | Maria Giulia Davighi Francesca Clemente Camilla Matassini Amelia Morrone Andrea Goti Macarena Martínez-Bailén Francesca Cardona |
| author_facet | Maria Giulia Davighi Francesca Clemente Camilla Matassini Amelia Morrone Andrea Goti Macarena Martínez-Bailén Francesca Cardona |
| author_sort | Maria Giulia Davighi |
| collection | DOAJ |
| description | 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 “<i>all-cis</i>” configuration at the hydroxy/amine-substituted stereocenters. The novel compounds were synthesized from a common carbohydrate-derived piperidinone intermediate <b>8</b>, through reductive amination or alkylation of the derived alcohol. In addition, the reaction of ketone <b>8</b> 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, <b>9</b>, <b>10</b>, and <b>12</b> behave as good inhibitors of lysosomal β-glucosidase (GCase) (IC<sub>50</sub> = 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. |
| first_indexed | 2024-03-10T15:53:04Z |
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| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T15:53:04Z |
| publishDate | 2020-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-95779178655840e78e997484b097941c2023-11-20T15:56:11ZengMDPI AGMolecules1420-30492020-10-012519452610.3390/molecules25194526Synthesis of “<i>All-Cis”</i> Trihydroxypiperidines from a Carbohydrate-Derived Ketone: Hints for the Design of New β-Gal and GCase InhibitorsMaria Giulia Davighi0Francesca Clemente1Camilla Matassini2Amelia Morrone3Andrea Goti4Macarena Martínez-Bailén5Francesca Cardona6Department of Chemistry “Ugo Schiff”, University of Firenze, via della Lastruccia 3-13, 50019 Sesto Fiorentino, ItalyDepartment of Chemistry “Ugo Schiff”, University of Firenze, via della Lastruccia 3-13, 50019 Sesto Fiorentino, ItalyDepartment of Chemistry “Ugo Schiff”, University of Firenze, via della Lastruccia 3-13, 50019 Sesto Fiorentino, ItalyPaediatric Neurology Unit and Laboratories, Neuroscience Department, Meyer Children’s Hospital and Department of Neurosciences, Pharmacology and Child Health, University of Florence, Viale Pieraccini 24, 50139 Firenze, ItalyDepartment of Chemistry “Ugo Schiff”, University of Firenze, via della Lastruccia 3-13, 50019 Sesto Fiorentino, ItalyDepartamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, García González 1, E-41012 Sevilla, SpainDepartment of Chemistry “Ugo Schiff”, University of Firenze, via della Lastruccia 3-13, 50019 Sesto Fiorentino, ItalyPharmacological 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 “<i>all-cis</i>” configuration at the hydroxy/amine-substituted stereocenters. The novel compounds were synthesized from a common carbohydrate-derived piperidinone intermediate <b>8</b>, through reductive amination or alkylation of the derived alcohol. In addition, the reaction of ketone <b>8</b> 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, <b>9</b>, <b>10</b>, and <b>12</b> behave as good inhibitors of lysosomal β-glucosidase (GCase) (IC<sub>50</sub> = 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.https://www.mdpi.com/1420-3049/25/19/4526synthesisazasugarsiminosugarslithium acetylideslysosomal enzyme inhibitorslysosomal storage disorders (LSDs) |
| spellingShingle | Maria Giulia Davighi Francesca Clemente Camilla Matassini Amelia Morrone Andrea Goti Macarena Martínez-Bailén Francesca Cardona Synthesis of “<i>All-Cis”</i> Trihydroxypiperidines from a Carbohydrate-Derived Ketone: Hints for the Design of New β-Gal and GCase Inhibitors Molecules synthesis azasugars iminosugars lithium acetylides lysosomal enzyme inhibitors lysosomal storage disorders (LSDs) |
| title | Synthesis of “<i>All-Cis”</i> Trihydroxypiperidines from a Carbohydrate-Derived Ketone: Hints for the Design of New β-Gal and GCase Inhibitors |
| title_full | Synthesis of “<i>All-Cis”</i> Trihydroxypiperidines from a Carbohydrate-Derived Ketone: Hints for the Design of New β-Gal and GCase Inhibitors |
| title_fullStr | Synthesis of “<i>All-Cis”</i> Trihydroxypiperidines from a Carbohydrate-Derived Ketone: Hints for the Design of New β-Gal and GCase Inhibitors |
| title_full_unstemmed | Synthesis of “<i>All-Cis”</i> Trihydroxypiperidines from a Carbohydrate-Derived Ketone: Hints for the Design of New β-Gal and GCase Inhibitors |
| title_short | Synthesis of “<i>All-Cis”</i> Trihydroxypiperidines from a Carbohydrate-Derived Ketone: Hints for the Design of New β-Gal and GCase Inhibitors |
| title_sort | synthesis of i all cis i trihydroxypiperidines from a carbohydrate derived ketone hints for the design of new β gal and gcase inhibitors |
| topic | synthesis azasugars iminosugars lithium acetylides lysosomal enzyme inhibitors lysosomal storage disorders (LSDs) |
| url | https://www.mdpi.com/1420-3049/25/19/4526 |
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