Rational design of a structural framework with potential use to develop chemical reagents that target and modulate multiple facets of Alzheimer's disease

Sanghyun Lee, Xueyun Zheng, Janarthanan Krishnamoorthy, Masha G Savelieff, Hyun Min Park, Jeffrey R Brender, Jin Hoon Kim, Jeffrey S Derrick, Akiko Kochi, Hyuck Jin Lee, Cheal Kim, Ayyalusamy Ramamoorthy, Michael T Bowers, Mi Hee Lim
Journal of the American Chemical Society 2014 January 8, 136 (1): 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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