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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• 作者：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
• 刊名：Journal of the American Chemical Society
• 出版年：2014
• 出版时间：January 8, 2014
• 年：2014
• 卷：136
• 期：1
• 页码：299-310
• 全文大小：598K
• ISSN：1520-5126

文摘

Alzheimer鈥檚 disease (AD) is characterized by multiple, intertwined pathological features, including amyloid-尾 (A尾) 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尾 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尾 (metal鈥揂尾) species, suppresses A尾 aggregation in vitro, and diminishes toxicity induced by A尾 and metal-treated A尾 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 A尾 and metal鈥揂尾 suggests the synergy of incorporating structural components for both metal chelation and A尾 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.