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...

Full description

Bibliographic Details
Main Authors: 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
Format: Article
Language:English
Published: MDPI AG 2020-09-01
Series:Molecules
Subjects:
Online Access:https://www.mdpi.com/1420-3049/25/17/4025
_version_ 1797554687388418048
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
format Article
id doaj.art-25403e0b400e40b799edabad23624a55
institution Directory Open Access Journal
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
work_keys_str_mv AT patrickweber mechanisticinsightsintothechaperoningofhumanlysosomalgalactosidaseactivityhighlyfunctionalizedaminocyclopentanesandici5asubstitutedderivativesof4iepiiisofagomine
AT martinthonhofer mechanisticinsightsintothechaperoningofhumanlysosomalgalactosidaseactivityhighlyfunctionalizedaminocyclopentanesandici5asubstitutedderivativesof4iepiiisofagomine
AT summeraverill mechanisticinsightsintothechaperoningofhumanlysosomalgalactosidaseactivityhighlyfunctionalizedaminocyclopentanesandici5asubstitutedderivativesof4iepiiisofagomine
AT gideonjdavies mechanisticinsightsintothechaperoningofhumanlysosomalgalactosidaseactivityhighlyfunctionalizedaminocyclopentanesandici5asubstitutedderivativesof4iepiiisofagomine
AT andresgonzalezsantana mechanisticinsightsintothechaperoningofhumanlysosomalgalactosidaseactivityhighlyfunctionalizedaminocyclopentanesandici5asubstitutedderivativesof4iepiiisofagomine
AT philippmuller mechanisticinsightsintothechaperoningofhumanlysosomalgalactosidaseactivityhighlyfunctionalizedaminocyclopentanesandici5asubstitutedderivativesof4iepiiisofagomine
AT seyedanasseri mechanisticinsightsintothechaperoningofhumanlysosomalgalactosidaseactivityhighlyfunctionalizedaminocyclopentanesandici5asubstitutedderivativesof4iepiiisofagomine
AT wendyaoffen mechanisticinsightsintothechaperoningofhumanlysosomalgalactosidaseactivityhighlyfunctionalizedaminocyclopentanesandici5asubstitutedderivativesof4iepiiisofagomine
AT bettinampabst mechanisticinsightsintothechaperoningofhumanlysosomalgalactosidaseactivityhighlyfunctionalizedaminocyclopentanesandici5asubstitutedderivativesof4iepiiisofagomine
AT eduardpaschke mechanisticinsightsintothechaperoningofhumanlysosomalgalactosidaseactivityhighlyfunctionalizedaminocyclopentanesandici5asubstitutedderivativesof4iepiiisofagomine
AT michaelschalli mechanisticinsightsintothechaperoningofhumanlysosomalgalactosidaseactivityhighlyfunctionalizedaminocyclopentanesandici5asubstitutedderivativesof4iepiiisofagomine
AT anatorvisco mechanisticinsightsintothechaperoningofhumanlysosomalgalactosidaseactivityhighlyfunctionalizedaminocyclopentanesandici5asubstitutedderivativesof4iepiiisofagomine
AT mariontschernutter mechanisticinsightsintothechaperoningofhumanlysosomalgalactosidaseactivityhighlyfunctionalizedaminocyclopentanesandici5asubstitutedderivativesof4iepiiisofagomine
AT christinatysoe mechanisticinsightsintothechaperoningofhumanlysosomalgalactosidaseactivityhighlyfunctionalizedaminocyclopentanesandici5asubstitutedderivativesof4iepiiisofagomine
AT wernerwindischhofer mechanisticinsightsintothechaperoningofhumanlysosomalgalactosidaseactivityhighlyfunctionalizedaminocyclopentanesandici5asubstitutedderivativesof4iepiiisofagomine
AT stephengwithers mechanisticinsightsintothechaperoningofhumanlysosomalgalactosidaseactivityhighlyfunctionalizedaminocyclopentanesandici5asubstitutedderivativesof4iepiiisofagomine
AT andreaswolfsgruber mechanisticinsightsintothechaperoningofhumanlysosomalgalactosidaseactivityhighlyfunctionalizedaminocyclopentanesandici5asubstitutedderivativesof4iepiiisofagomine
AT tanjamwrodnigg mechanisticinsightsintothechaperoningofhumanlysosomalgalactosidaseactivityhighlyfunctionalizedaminocyclopentanesandici5asubstitutedderivativesof4iepiiisofagomine
AT arnoldestutz mechanisticinsightsintothechaperoningofhumanlysosomalgalactosidaseactivityhighlyfunctionalizedaminocyclopentanesandici5asubstitutedderivativesof4iepiiisofagomine