1. Mechanistic Insights into the Chaperoning of Human Lysosomal-Galactosidase Activity: Highly Functionalized Aminocyclopentanes and C -5a-Substituted Derivatives of 4- epi -Isofagomine.
- Author
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Weber P, Thonhofer M, Averill S, Davies GJ, Santana AG, Müller P, Nasseri SA, Offen WA, Pabst BM, Paschke E, Schalli M, Torvisco A, Tschernutter M, Tysoe C, Windischhofer W, Withers SG, Wolfsgruber A, Wrodnigg TM, and Stütz AE
- Subjects
- Crystallization, Cyclopentanes chemical synthesis, Cyclopentanes chemistry, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Galactosidases antagonists & inhibitors, Humans, Imino Pyranoses chemical synthesis, Imino Pyranoses chemistry, Ligands, Lysosomes drug effects, Molecular Conformation, Mutant Proteins metabolism, Cyclopentanes pharmacology, Galactosidases metabolism, Imino Pyranoses pharmacology, Lysosomes enzymology, Molecular Chaperones metabolism
- 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 G
M1 -gangliosidosis and Morquio B disease.- Published
- 2020
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