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

Patrick Weber, Martin Simon 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 Gomez, Marion Tschernutter, Christina Tysoe, Werner Windischhofer, Stephen G Withers, Andreas Wolfsgruber, Tanja Maria Wrodnigg, Arnold Stütz*

*Korrespondierende/r Autor/in für diese Arbeit

Publikation: Beitrag in einer FachzeitschriftArtikel

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
Originalspracheenglisch
Aufsatznummer4025
Seitenumfang25
FachzeitschriftMolecules
Jahrgang25
Ausgabenummer17
DOIs
PublikationsstatusVeröffentlicht - 2020

ASJC Scopus subject areas

  • !!Drug Discovery
  • Analytische Chemie
  • !!Chemistry (miscellaneous)
  • !!Molecular Medicine
  • !!Physical and Theoretical Chemistry
  • !!Pharmaceutical Science
  • Organische Chemie

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