title: Rational design of a structural framework with potential use to develop chemical reagents that target and modulate multiple facets of Alzheimer's disease.
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 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.
authors.affiliation: Life Sciences Institute, University of Michigan , Ann Arbor, Michigan 48109-2216, United States.
authors.forename: Sanghyun
authors.initials: S
authors.lastname: Lee
authors.forename: Xueyun
authors.initials: X
authors.lastname: Zheng
authors.forename: Janarthanan
authors.initials: J
authors.lastname: Krishnamoorthy
authors.forename: Masha G
authors.initials: MG
authors.lastname: Savelieff
authors.forename: Hyun Min
authors.initials: HM
authors.lastname: Park
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Brender
authors.forename: Jin Hoon
authors.initials: JH
authors.lastname: Kim
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Derrick
authors.forename: Akiko
authors.initials: A
authors.lastname: Kochi
authors.forename: Hyuck Jin
authors.initials: HJ
authors.lastname: Lee
authors.forename: Cheal
authors.initials: C
authors.lastname: Kim
authors.forename: Ayyalusamy
authors.initials: A
authors.lastname: Ramamoorthy
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bowers
authors.forename: Mi Hee
authors.initials: MH
authors.lastname: Lim
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology; D003300:Copper / Q000737:chemistry; D016503:Drug Delivery Systems; D015195:Drug Design; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D017382:Reactive Oxygen Species; D015032:Zinc / Q000737:chemistry
chemical_list: D000975:Antioxidants; D002614:Chelating Agents; D008024:Ligands; D017382:Reactive Oxygen Species; D003300:Copper; D015032:Zinc