Tuning Structures and Properties for Developing Novel Chemical Tools toward Distinct Pathogenic Elements in Alzheimer's Disease

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Multiple pathogenic factors [e.g., amyloid-beta (A beta), metal ions, metal-bound A beta (metal-A beta), reactive oxygen species (ROS)] are found in the brain of patients with Alzheimer's disease (AD). In order to elucidate the roles of pathological elements in AD, chemical tools able to regulate their activities would be valuable. Due to the complicated link among multiple pathological factors, however, it has been challenging to invent such chemical tools. Herein, we report novel small molecules as chemical tools toward modulation of single or multiple target(s), designed via a rational structure-property-directed strategy. The chemical properties (e.g., oxidation potentials) of our molecules and their coverage of reactivities toward the pathological targets were successfully differentiated through a minor structural variation [i.e., replacement of one nitrogen (N) or sulfur (S) donor atom in the framework]. Among our compounds (1-3), 1 with the lowest oxidation potential is able to noticeably modify the aggregation of both metal-free A beta and metal A beta, as well as scavenge free radicals. Compound 2 with the moderate oxidation potential significantly alters the aggregation of Cu(II) A beta(42). The hardly oxidizable compound, 3, relative to 1 and 2, indicates no noticeable interactions with all pathogenic factors, including metal-free A beta, metal-A beta, and free radicals. Overall, our studies demonstrate that the design of small molecules as chemical tools able to control distinct pathological components could be achieved via fine-tuning of structures and properties.
Publisher
AMER CHEMICAL SOC
Issue Date
2018-04
Language
English
Article Type
Article
Keywords

AMYLOID-BETA-PEPTIDE; METAL-CATALYZED OXIDATION; A-BETA; ANTIOXIDANT CAPACITY; SMALL MOLECULES; CYCLIC VOLTAMMETRY; AGGREGATION; NEUROTOXICITY; INHIBITORS; DESIGN

Citation

ACS CHEMICAL NEUROSCIENCE, v.9, no.4, pp.800 - 808

ISSN
1948-7193
DOI
10.1021/acschemneuro.7b00454
URI
http://hdl.handle.net/10203/244701
Appears in Collection
CH-Journal Papers(저널논문)
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