期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 136, 期 1, 页码 299-310出版社
AMER CHEMICAL SOC
DOI: 10.1021/ja409801p
关键词
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资金
- National Institutes of Health [GM084018, GM095640, RR023597, AG047116]
- American Heart Association
- Ruth K. Broad Biomedical Foundation
- Alfred P. Sloan Fellowship
- Rush Alzheimer's Disease Core Center [P30AG010161]
- National Science Foundation [CHE-1253155]
- Research Fund of UNIST (Ulsan National Institute of Science and Technology) [1.130068.01]
- Ministry of Education, Science and Technology [2012001725]
Alzheimer's disease (AD) is characterized by multiple, intertwined pathological features, including amyloid-beta (A beta) aggregation, metal ion dyshomeostasis, and oxidative stress. We report a novel compound (ML) prototype of a rationally designed molecule obtained by integrating structural elements for A beta aggregation control, metal chelation, reactive oxygen species (ROS) regulation, and antioxidant activity within a single molecule. Chemical, biochemical, ion mobility mass spectrometric, and NMR studies indicate that the compound ML targets metal-free and metal-bound A beta (metal-A beta) species, suppresses A beta aggregation in vitro, and diminishes toxicity induced by A beta and metal-treated A beta in living cells. Comparison of ML to its structural moieties (i.e., 4-(dimethylamino)phenol (DAP) and (8-aminoquinolin-2-yl)methanol (I)) for reactivity with A beta and metal-A beta suggests the synergy of incorporating structural components for both metal chelation and A beta interaction. Moreover, ML is water-soluble and potentially brain permeable, as well as regulates the formation and presence of free radicals. Overall, we demonstrate that a rational structure-based design strategy can generate a small molecule that can target and modulate multiple factors, providing a new tool to uncover and address AD complexity.
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