Selective Targeting of the Interconversion between Glucosylceramide and Ceramide by Scaffold Tailoring of Iminosugar Inhibitors
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemical Synthesis
2.2. Effect of Iminosugars on Cell Viability
2.3. Effect of Iminosugars on GCS Inhibition
2.4. Effect of Iminosugars on GBA Inhibition
2.5. Molecular Docking
2.6. GBA Pharmacological Chaperone Activity
2.6.1. Preliminary In Vitro Studies
2.6.2. Enhancement of GBA Activity in GD Patient Cells
3. Discussion
4. Materials and Methods
4.1. General Methods
4.2. Synthesis of Compounds 6b and 8
4.3. Cellular Inhibition Assays against Glucosylceramide Synthase
4.4. Inhibition Assays against Recombinant β-glucocerebrosidase.
4.5. Molecular Docking
4.6. Thermal Stabilization Assay Using Recombinant β-Glucocerebrosidase
4.7. Culture and Cell Viability Assays
4.8. Assay of β-glucocerebrosidase Activity
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References and Note
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Sample Availability: Samples of the compounds are not available from the authors. |
Cell Viability 1 | Murine Melanoma 2 | Human Fibroblast 3 | Gaucher Fibroblast 4 |
---|---|---|---|
| 85% | ND 5 | ND |
| 14% | 12.5% | 14% |
| 16% | 13.7% | 14% |
| 85% | 91% | 84% |
| ND | 99% | 94% |
Enzyme Inhibition | GCS 1 | GBA 2 |
---|---|---|
| 15% | >8000 nM |
| 47% | 4200 nM |
| 20% | 6000 nM |
| NI 3 | 108 nM |
| NI | 11 nM |
| ND 4 | 4 nM |
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Baudoin-Dehoux, C.; Castellan, T.; Rodriguez, F.; Rives, A.; Stauffert, F.; Garcia, V.; Levade, T.; Compain, P.; Génisson, Y. Selective Targeting of the Interconversion between Glucosylceramide and Ceramide by Scaffold Tailoring of Iminosugar Inhibitors. Molecules 2019, 24, 354. https://doi.org/10.3390/molecules24020354
Baudoin-Dehoux C, Castellan T, Rodriguez F, Rives A, Stauffert F, Garcia V, Levade T, Compain P, Génisson Y. Selective Targeting of the Interconversion between Glucosylceramide and Ceramide by Scaffold Tailoring of Iminosugar Inhibitors. Molecules. 2019; 24(2):354. https://doi.org/10.3390/molecules24020354
Chicago/Turabian StyleBaudoin-Dehoux, Cécile, Tessa Castellan, Frédéric Rodriguez, Arnaud Rives, Fabien Stauffert, Virginie Garcia, Thierry Levade, Philippe Compain, and Yves Génisson. 2019. "Selective Targeting of the Interconversion between Glucosylceramide and Ceramide by Scaffold Tailoring of Iminosugar Inhibitors" Molecules 24, no. 2: 354. https://doi.org/10.3390/molecules24020354