Minimalistic Principles for Designing Small Molecules with Multiple Reactivities against Pathological Factors in Dementia.
J Am Chem Soc
; 142(18): 8183-8193, 2020 05 06.
Article
em En
| MEDLINE
| ID: mdl-32233474
ABSTRACT
Multiple pathogenic elements, including reactive oxygen species, amyloidogenic proteins, and metal ions, are associated with the development of neurodegenerative disorders. We report minimalistic redox-based principles for preparing compact aromatic compounds by derivatizing the phenylene moiety with various functional groups. These molecular agents display enhanced reactivities against multiple targets such as free radicals, metal-free amyloid-ß (Aß), and metal-bound Aß that are implicated in the most common form of dementia, Alzheimer's disease (AD). Mechanistic studies reveal that the redox properties of these reagents are essential for their function. Specifically, they engage in oxidative reactions with metal-free and metal-bound Aß, leading to chemical modifications of the Aß peptides to form covalent adducts that alter the aggregation of Aß. Moreover, the administration of the most promising candidate significantly attenuates the amyloid pathology in the brains of AD transgenic mice and improves their cognitive defects. Our studies demonstrate an efficient and effective redox-based strategy for incorporating multiple functions into simple molecular reagents.
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Base de dados:
MEDLINE
Assunto principal:
Peptídeos beta-Amiloides
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Bibliotecas de Moléculas Pequenas
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Doença de Alzheimer
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Hidrocarbonetos Aromáticos
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article