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Mechanistic Insights into the Chaperoning of Human Lysosomal-Galactosidase Activity: Highly Functionalized Aminocyclopentanes and C-5a-Substituted Derivatives of 4-epi-Isofagomine Weber, Patrick; Thonhofer, Martin; Averill, Summer; Davies, Gideon J.; Santana, Andres Gonzalez; Müller, Philipp; Nasseri, Seyed A.; Offen, Wendy A.; Pabst, Bettina M.; Paschke, Eduard; Schalli, Michael; Torvisco, Ana; Tschernutter, Marion; Tysoe, Christina; Windischhofer, Werner; Withers, Stephen G.; Wolfsgruber, Andreas; Wrodnigg, Tanja M.; Stütz, Arnold E.
Abstract
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.
Item Metadata
| Title |
Mechanistic Insights into the Chaperoning of Human Lysosomal-Galactosidase Activity: Highly Functionalized Aminocyclopentanes and C-5a-Substituted Derivatives of 4-epi-Isofagomine
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| Creator |
Weber, Patrick; Thonhofer, Martin; Averill, Summer; Davies, Gideon J.; Santana, Andres Gonzalez; Müller, Philipp; Nasseri, Seyed A.; Offen, Wendy A.; Pabst, Bettina M.; Paschke, Eduard; Schalli, Michael; Torvisco, Ana; Tschernutter, Marion; Tysoe, Christina; Windischhofer, Werner; Withers, Stephen G.; Wolfsgruber, Andreas; Wrodnigg, Tanja M.; Stütz, Arnold E.
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| Publisher |
Multidisciplinary Digital Publishing Institute
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| Date Issued |
2020-09-03
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| Description |
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.
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| Subject | |
| Genre | |
| Type | |
| Language |
eng
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| Date Available |
2020-09-08
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| Provider |
Vancouver : University of British Columbia Library
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| Rights |
CC BY 4.0
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| DOI |
10.14288/1.0394263
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| URI | |
| Affiliation | |
| Citation |
Molecules 25 (17): 4025 (2020)
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| Publisher DOI |
10.3390/molecules25174025
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| Peer Review Status |
Reviewed
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| Scholarly Level |
Faculty
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| Rights URI | |
| Aggregated Source Repository |
DSpace
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Item Media
Item Citations and Data
Rights
CC BY 4.0