Mechanistic Insights into the Chaperoning of Human Lysosomal-Galactosidase Activity: Highly Functionalized Aminocyclopentanes and <i>C</i>-5a-Substituted Derivatives of 4-<i>epi</i>-Isofagomine
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...
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2020-09-01
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author | Patrick Weber Martin Thonhofer Summer Averill Gideon J. Davies Andres Gonzalez 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 Arnold E. Stütz |
author_facet | Patrick Weber Martin Thonhofer Summer Averill Gideon J. Davies Andres Gonzalez 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 Arnold E. Stütz |
author_sort | Patrick Weber |
collection | DOAJ |
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-<span style="font-variant: small-caps;">d</span>-galactosidase inhibitor 4-<i>epi</i>-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 G<sub>M1</sub>-gangliosidosis and Morquio B disease. |
first_indexed | 2024-03-10T16:35:35Z |
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issn | 1420-3049 |
language | English |
last_indexed | 2024-03-10T16:35:35Z |
publishDate | 2020-09-01 |
publisher | MDPI AG |
record_format | Article |
series | Molecules |
spelling | doaj.art-25403e0b400e40b799edabad23624a552023-11-20T12:27:59ZengMDPI AGMolecules1420-30492020-09-012517402510.3390/molecules25174025Mechanistic Insights into the Chaperoning of Human Lysosomal-Galactosidase Activity: Highly Functionalized Aminocyclopentanes and <i>C</i>-5a-Substituted Derivatives of 4-<i>epi</i>-IsofagominePatrick Weber0Martin Thonhofer1Summer Averill2Gideon J. Davies3Andres Gonzalez Santana4Philipp Müller5Seyed A. Nasseri6Wendy A. Offen7Bettina M. Pabst8Eduard Paschke9Michael Schalli10Ana Torvisco11Marion Tschernutter12Christina Tysoe13Werner Windischhofer14Stephen G. Withers15Andreas Wolfsgruber16Tanja M. Wrodnigg17Arnold E. Stütz18Glycogroup, Institute of Chemistry and Technology of Biobased Systems, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, AustriaGlycogroup, Institute of Chemistry and Technology of Biobased Systems, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, AustriaGlycogroup, Institute of Chemistry and Technology of Biobased Systems, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, AustriaDepartment of Chemistry, University of York, Heslington, York YO10 5DD, North Yorkshire, UKChemistry Department, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, CanadaInstitute of Inorganic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, AustriaChemistry Department, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, CanadaDepartment of Chemistry, University of York, Heslington, York YO10 5DD, North Yorkshire, UKLaboratory of Metabolic Diseases, Department of Pediatrics, MedUni Graz, Auenbruggerplatz 30, A-8036 Graz, AustriaLaboratory of Metabolic Diseases, Department of Pediatrics, MedUni Graz, Auenbruggerplatz 30, A-8036 Graz, AustriaGlycogroup, Institute of Chemistry and Technology of Biobased Systems, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, AustriaInstitute of Inorganic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, AustriaLaboratory of Metabolic Diseases, Department of Pediatrics, MedUni Graz, Auenbruggerplatz 30, A-8036 Graz, AustriaChemistry Department, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, CanadaLaboratory of Metabolic Diseases, Department of Pediatrics, MedUni Graz, Auenbruggerplatz 30, A-8036 Graz, AustriaChemistry Department, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, CanadaGlycogroup, Institute of Chemistry and Technology of Biobased Systems, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, AustriaGlycogroup, Institute of Chemistry and Technology of Biobased Systems, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, AustriaGlycogroup, Institute of Chemistry and Technology of Biobased Systems, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, AustriaGlycosidase 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-<span style="font-variant: small-caps;">d</span>-galactosidase inhibitor 4-<i>epi</i>-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 G<sub>M1</sub>-gangliosidosis and Morquio B disease.https://www.mdpi.com/1420-3049/25/17/4025iminoalditol4-<i>epi</i>-isofagominecarbasugaraminocyclopentanegalactosidase inhibitorpharmacological chaperone |
spellingShingle | Patrick Weber Martin Thonhofer Summer Averill Gideon J. Davies Andres Gonzalez 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 Arnold E. Stütz Mechanistic Insights into the Chaperoning of Human Lysosomal-Galactosidase Activity: Highly Functionalized Aminocyclopentanes and <i>C</i>-5a-Substituted Derivatives of 4-<i>epi</i>-Isofagomine Molecules iminoalditol 4-<i>epi</i>-isofagomine carbasugar aminocyclopentane galactosidase inhibitor pharmacological chaperone |
title | Mechanistic Insights into the Chaperoning of Human Lysosomal-Galactosidase Activity: Highly Functionalized Aminocyclopentanes and <i>C</i>-5a-Substituted Derivatives of 4-<i>epi</i>-Isofagomine |
title_full | Mechanistic Insights into the Chaperoning of Human Lysosomal-Galactosidase Activity: Highly Functionalized Aminocyclopentanes and <i>C</i>-5a-Substituted Derivatives of 4-<i>epi</i>-Isofagomine |
title_fullStr | Mechanistic Insights into the Chaperoning of Human Lysosomal-Galactosidase Activity: Highly Functionalized Aminocyclopentanes and <i>C</i>-5a-Substituted Derivatives of 4-<i>epi</i>-Isofagomine |
title_full_unstemmed | Mechanistic Insights into the Chaperoning of Human Lysosomal-Galactosidase Activity: Highly Functionalized Aminocyclopentanes and <i>C</i>-5a-Substituted Derivatives of 4-<i>epi</i>-Isofagomine |
title_short | Mechanistic Insights into the Chaperoning of Human Lysosomal-Galactosidase Activity: Highly Functionalized Aminocyclopentanes and <i>C</i>-5a-Substituted Derivatives of 4-<i>epi</i>-Isofagomine |
title_sort | mechanistic insights into the chaperoning of human lysosomal galactosidase activity highly functionalized aminocyclopentanes and i c i 5a substituted derivatives of 4 i epi i isofagomine |
topic | iminoalditol 4-<i>epi</i>-isofagomine carbasugar aminocyclopentane galactosidase inhibitor pharmacological chaperone |
url | https://www.mdpi.com/1420-3049/25/17/4025 |
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