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Minor Structural Variations of Small Molecules Tune Regulatory Activities Towards Pathological Factors in Alzheimer’s Disease

Author(s)
Beck, Michael W.Derrick, Jeffrey S.Suh, Jong-MinKim, MingeunKorshavn, Kyle J.Kerr, Richard A.Cho, Woo JongLarsen, Scott D.Ruotolo, Brandon T.Ramamoorthy, AyyalusamyLim, Mi Hee
Issued Date
2017-11
DOI
10.1002/cmdc.201700456
URI
https://scholarworks.unist.ac.kr/handle/201301/22976
Fulltext
http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201700456/abstract
Citation
CHEMMEDCHEM, v.12, no.22, pp.1828 - 1838
Abstract
Chemical tools have been valuable for establishing a better understanding of the relationships between metal ion dyshomeostasis, the abnormal aggregation and accumulation of amyloid-β (Aβ), and oxidative stress in Alzheimer's disease (AD). Still, very little information is available to correlate the structures of chemical tools with specific reactivities used to uncover such relationships. Recently, slight structural variations to the framework of a chemical tool were found to drastically determine the tool's reactivities toward multiple pathological facets to various extents. Herein, we report our rational design and characterization of a structural series to illustrate the extent to which the reactivities of small molecules vary toward different targets as a result of minor structural modifications. These compounds were rationally and systematically modified based on consideration of properties, including ionization potentials and metal binding, to afford their desired reactivities with metal-free or metal-bound Aβ, reactive oxygen species (ROS), and free organic radicals. Our results show that although small molecules are structurally similar, they can interact with multiple factors associated with AD pathogenesis and alleviate their reactivities to different degrees. Together, our studies demonstrate the rational structure-directed design that can be used to develop chemical tools capable of regulating individual or interrelated pathological features in AD.
Publisher
WILEY-V C H VERLAG GMBH
ISSN
1860-7179
Keyword (Author)
amyloid-free radicalsmetal ionssmall moleculesstructure-activity relationships
Keyword
AMYLOID-BETAMASS-SPECTROMETRYNEURODEGENERATIVE DISEASESOXIDATIVE STRESSMETAL-IONSTARGETPEPTIDESDESIGNAGGREGATIONASSEMBLIES

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