1. Rational Design of a Structural Framework with Potential Use to Develop Chemical Reagents That Target and Modulate Multiple Facets of Alzheimer's Disease.
- Author
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Sanghyun Lee, Xueyun Zheng, Janarthanan Krishnamoorthy, Savelieff, Masha G., Hyun Min Park, Brender, Jeffrey R., Jin Hoon Kim, Derrick, Jeffrey S., Kochi, Akiko, Hyuck Jin Lee, Cheal Kim, Ayyalusamy Ramamoorthy, Bowers, Michael T., and Mi Hee Lim
- Subjects
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CHEMICAL reagents , *ALZHEIMER'S disease , *AMYLOID beta-protein , *METAL ions , *OXIDATIVE stress , *CHELATION , *REACTIVE oxygen species , *ION mobility spectroscopy - Abstract
Alzheimer's disease (AD) is characterized by multiple, intertwined pathological features, including amyloid-β (Aβ) 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 Aβ 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 metalfree and metal-bound Aβ (metal-Aβ) species, suppresses Aβ aggregation in vitro, and diminishes toxicity induced by Aβ and metal-treated Aβ in living cells. Comparison of ML to its structural moieties (i.e., 4-(dimethylamino)phenol (DAP) and (8- aminoquinolin-2-yl)methanol (1)) for reactivity with Aβ and metal-Aβ suggests the synergy of incorporating structural components for both metal chelation and Aβ 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. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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