A Glutathione Derivative with Chelating and in vitro Neuroprotective Activities: Synthesis, Physicochemical Properties, and Biological Evaluation

Metal‐ion dysregulation and oxidative stress have been linked to the progressive neurological decline associated with neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Herein we report the synthesis and chelating, antioxidant, and in vitro neuroprotective activities of a nove...

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Bibliographic Details
Published in:ChemMedChem 2013-11, Vol.8 (11), p.1818-1829
Main Authors: Cacciatore, Ivana, Cornacchia, Catia, Fornasari, Erika, Baldassarre, Leonardo, Pinnen, Francesco, Sozio, Piera, Di Stefano, Antonio, Marinelli, Lisa, Dean, Annalisa, Fulle, Stefania, Di Filippo, Ester Sara, La Rovere, Rita Maria Laura, Patruno, Antonia, Ferrone, Alessio, Di Marco, Valerio
Format: Article
Language:eng ; ger
Subjects:
8-Hydroxyquinoline
8-hydroxyquinolines
antioxidants
Antioxidants - chemistry
Antioxidants - pharmacology
Cell Line
Cell Survival - drug effects
Chelating Agents - chemical synthesis
Chelating Agents - chemistry
Chelating Agents - pharmacology
chelation therapy
glutathione
Glutathione - chemistry
Glutathione - pharmacology
Humans
Hydrogen-Ion Concentration
Molecular Structure
Neuroblastoma - pathology
neurodegenerative diseases
Neuroprotective Agents - chemical synthesis
Neuroprotective Agents - chemistry
Neuroprotective Agents - pharmacology
Oxyquinoline - chemistry
peptides
Reactive Oxygen Species
Solubility
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Summary:Metal‐ion dysregulation and oxidative stress have been linked to the progressive neurological decline associated with neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Herein we report the synthesis and chelating, antioxidant, and in vitro neuroprotective activities of a novel derivative of glutathione, GS(HQ)H, endowed with an 8‐hydroxyquinoline group as a metal‐chelating moiety. In vitro results showed that GS(HQ)H may be stable enough to be absorbed unmodified and arrive intact to the blood–brain barrier, that it may be able to remove CuII and ZnII from the Aβ peptide without causing any copper or zinc depletion in vivo, and that it protects SHSY‐5Y human neuroblastoma cells against H2O2‐ and 6‐OHDA‐induced damage. Together, these findings suggest that GS(HQ)H could be a potential neuroprotective agent for the treatment of neurodegenerative diseases in which a lack of metal homeostasis has been reported as a key factor. Multi‐target multitasking: We report the synthesis of a novel and chemically stable S‐hydroxyquinoline glutathione derivative. This compound was shown to prevent H2O2‐ and 6‐OHDA‐mediated oxidative stress in in vitro models and to partially and quantitatively remove CuII and ZnII, respectively, from the Aβ peptide.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.201300295