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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-β (Aβ), and metal-bound Aβ 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 Aβ, leading to chemical modifications of the Aβ peptides to form covalent adducts that alter the aggregation of Aβ. 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.

Affiliations

Mingeun Kim  1 , Juhye Kang  1 , Misun Lee  1   2 , Jiyeon Han  1 , Geewoo Nam  2 , Eunyoung Tak  3   4 , Min Sun Kim  3   4 , Hyuck Jin Lee  5 , Eunju Nam  1 , Jiyong Park  1   6 , Soo Jin Oh  3   4 , Ji-Yoon Lee  3   4 , Joo-Yong Lee  3   4 , Mu-Hyun Baik  1   6 , Mi Hee Lim  1
1 Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
2 Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
3 Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Republic of Korea.
4 Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
5 Department of Chemistry Education, Kongju National University, Gongju 32588, Republic of Korea.
6 Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Republic of Korea.