Rational design of a structural framework with potential use to develop chemical reagents that target and modulate multiple facets of Alzheimer's disease
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- Rational design of a structural framework with potential use to develop chemical reagents that target and modulate multiple facets of Alzheimer's disease
- Lee, Sanghyun; Zheng, Xueyun; Krishnamoorthy, Janarthanan; Savelieff, Masha G.; Park, Hyun Min; Brender, Jeffrey R.; Kim, Jin Hoon; Derrick, Jeffrey S.; Kochi, Akiko; Lee, Hyuck Jin; Kim, Cheal; Ramamoorthy, Ayyalusamy; Bowers, Michael T.; Lim, Mi Hee
- Issue Date
- AMER CHEMICAL SOC
- JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, v.136, no.1, pp.299 - 310
- 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 metal-free 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.
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