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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.
- Source :
-
Molecules (Basel, Switzerland) [Molecules] 2020 Sep 03; Vol. 25 (17). Date of Electronic Publication: 2020 Sep 03. - Publication Year :
- 2020
-
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 <subscript>M1</subscript> -gangliosidosis and Morquio B disease.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1420-3049
- Volume :
- 25
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Molecules (Basel, Switzerland)
- Publication Type :
- Academic Journal
- Accession number :
- 32899288
- Full Text :
- https://doi.org/10.3390/molecules25174025