Minimalistic Principles for Designing Small Molecules with Multiple Reactivities against Pathological Factors in Dementia

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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-beta (A beta), and metal-bound A beta 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 A beta, leading to chemical modifications of the A beta peptides to form covalent adducts that alter the aggregation of A beta. 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.
Publisher
AMER CHEMICAL SOC
Issue Date
2020-05
Language
English
Article Type
Article
Citation

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, v.142, no.18, pp.8183 - 8193

ISSN
0002-7863
DOI
10.1021/jacs.9b13100
URI
http://hdl.handle.net/10203/274704
Appears in Collection
CH-Journal Papers(저널논문)
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