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Article

Mechanistic Insights into the Chaperoning of Human Lysosomal-Galactosidase Activity: Highly Functionalized Aminocyclopentanes and C-5a-Substituted Derivatives of 4-epi-Isofagomine

1
Glycogroup, Institute of Chemistry and Technology of Biobased Systems, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria
2
Department of Chemistry, University of York, Heslington, York YO10 5DD, North Yorkshire, UK
3
Chemistry Department, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada
4
Institute of Inorganic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria
5
Laboratory of Metabolic Diseases, Department of Pediatrics, MedUni Graz, Auenbruggerplatz 30, A-8036 Graz, Austria
*
Author to whom correspondence should be addressed.
These authors contributed equally to this paper.
Academic Editor: László Somsák
Molecules 2020, 25(17), 4025; https://doi.org/10.3390/molecules25174025
Received: 29 July 2020 / Revised: 24 August 2020 / Accepted: 25 August 2020 / Published: 3 September 2020
(This article belongs to the Special Issue Targeting Carbohydrate–Protein Interactions)
Glycosidase inhibitors have shown great potential as pharmacological chaperones for lysosomal storage diseases. In light of this, a series of new cyclopentanoid β-galactosidase inhibitors were prepared and their inhibitory and pharmacological chaperoning activities determined and compared with those of lipophilic analogs of the potent β-d-galactosidase inhibitor 4-epi-isofagomine. Structure-activity relationships were investigated by X-ray crystallography as well as by alterations in the cyclopentane moiety such as deoxygenation and replacement by fluorine of a “strategic” hydroxyl group. New compounds have revealed highly promising activities with a range of β-galactosidase-compromised human cell lines and may serve as leads towards new pharmacological chaperones for GM1-gangliosidosis and Morquio B disease. View Full-Text
Keywords: iminoalditol; 4-epi-isofagomine; carbasugar; aminocyclopentane; galactosidase inhibitor; pharmacological chaperone; GM1-gangliosidosis iminoalditol; 4-epi-isofagomine; carbasugar; aminocyclopentane; galactosidase inhibitor; pharmacological chaperone; GM1-gangliosidosis
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MDPI and ACS Style

Weber, P.; Thonhofer, M.; Averill, S.; Davies, G.J.; Santana, A.G.; Müller, P.; Nasseri, S.A.; Offen, W.A.; Pabst, B.M.; Paschke, E.; Schalli, M.; Torvisco, A.; Tschernutter, M.; Tysoe, C.; Windischhofer, W.; Withers, S.G.; Wolfsgruber, A.; Wrodnigg, T.M.; Stütz, A.E. Mechanistic Insights into the Chaperoning of Human Lysosomal-Galactosidase Activity: Highly Functionalized Aminocyclopentanes and C-5a-Substituted Derivatives of 4-epi-Isofagomine. Molecules 2020, 25, 4025. https://doi.org/10.3390/molecules25174025

AMA Style

Weber P, Thonhofer M, Averill S, Davies GJ, Santana AG, Müller P, Nasseri SA, Offen WA, Pabst BM, Paschke E, Schalli M, Torvisco A, Tschernutter M, Tysoe C, Windischhofer W, Withers SG, Wolfsgruber A, Wrodnigg TM, Stütz AE. Mechanistic Insights into the Chaperoning of Human Lysosomal-Galactosidase Activity: Highly Functionalized Aminocyclopentanes and C-5a-Substituted Derivatives of 4-epi-Isofagomine. Molecules. 2020; 25(17):4025. https://doi.org/10.3390/molecules25174025

Chicago/Turabian Style

Weber, Patrick, Martin Thonhofer, Summer Averill, Gideon J. Davies, Andres G. Santana, Philipp Müller, Seyed A. Nasseri, Wendy A. Offen, Bettina M. Pabst, Eduard Paschke, Michael Schalli, Ana Torvisco, Marion Tschernutter, Christina Tysoe, Werner Windischhofer, Stephen G. Withers, Andreas Wolfsgruber, Tanja M. Wrodnigg, and Arnold E. Stütz 2020. "Mechanistic Insights into the Chaperoning of Human Lysosomal-Galactosidase Activity: Highly Functionalized Aminocyclopentanes and C-5a-Substituted Derivatives of 4-epi-Isofagomine" Molecules 25, no. 17: 4025. https://doi.org/10.3390/molecules25174025

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