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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.

ABSTRACT: Glycosidase inhibitors have shown great potential as pharmacological chaperones for lysosomal storage diseases. In light of this, a series of new cyclopentanoid ?-galactosidase inhibitors were prepared and their inhibitory and pharmacological chaperoning activities determined and compared with those of lipophilic analogs of the potent ?-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 ?-galactosidase-compromised human cell lines and may serve as leads towards new pharmacological chaperones for GM1-gangliosidosis and Morquio B disease.

SUBMITTER: Weber P 

PROVIDER: S-EPMC7504770 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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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.

Weber Patrick P   Thonhofer Martin M   Averill Summer S   Davies Gideon J GJ   Santana Andres Gonzalez AG   Müller Philipp P   Nasseri Seyed A SA   Offen Wendy A WA   Pabst Bettina M BM   Paschke Eduard E   Schalli Michael M   Torvisco Ana A   Tschernutter Marion M   Tysoe Christina C   Windischhofer Werner W   Withers Stephen G SG   Wolfsgruber Andreas A   Wrodnigg Tanja M TM   Stütz Arnold E AE  

Molecules (Basel, Switzerland) 20200903 17

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-<i>epi</i>-isofagomine. Structure-activity relationships were investigated by X-ray crystallography as well as by alterations in the  ...[more]

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