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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

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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
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    † Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109-2216, United States
    ‡ Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106-9510, United States
    § Biophysics, University of Michigan, Ann Arbor, Michigan 48109-1055, United States
    ⊥ Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055, United States
    Department of Chemistry, Seoul National University of Science and Technology, Seoul 139-743, Korea
    ∥ School of Nano-Bioscience and Chemical Engineering, Ulsan National Institute of Science and Technology (UNIST), Ulsan 689-798, Korea
    A. Ramamoorthy. E-mail: [email protected]
    M. T. Bowers. E-mail: [email protected]
    M. H. Lim. E-mail: [email protected]
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    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 2014, 136, 1, 299–310
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    https://doi.org/10.1021/ja409801p
    Published December 27, 2013
    Copyright © 2013 American Chemical Society
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    Abstract

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    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.

    Copyright © 2013 American Chemical Society

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    Additional mass spectra, UV–vis spectra, docking diagrams, cluster energy analyses, electrophoresis visualizations, TEM images, and selectivity, speciation, and cytotoxicity, and inhibitory activity studies. This material is available free of charge via the Internet at http://pubs.acs.org.

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    Cite this: J. Am. Chem. Soc. 2014, 136, 1, 299–310
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