title: New Hydroxyquinoline-Based Derivatives as Potent Modulators of Amyloid-β Aggregations.
abstract: Copper and zinc have been found to contribute to the burden of amyloid-β (Aβ) aggregations in neurodegenerative Alzheimer's disease (AD). Dysregulation of these metals leads to the generation of reactive oxygen species (ROS) and eventually results in oxidative damage and accumulation of the Aβ peptide, which are the key elements of the disease. Aiming to pursue the discovery of new modulators for the disease, we here rationally focused on conjugating the core hydroxyquinoline of the metal-protein attenuating compound PBT2 and the N-methylanilide analogous moiety of the Aβ imaging agent to build a new type of multi-target modulators of Aβ aggregations. We found that the N,N-dimethylanilinyl imines 7a, 8a, and the corresponding amines 7b, 8b exerted efficient inhibition of Cu(2+) - or Zn(2+) -induced Aβ aggregations and significant disassembly of metal-mediated Aβ aggregated fibrils. Further, 7a and 7b also exhibited significant ROC scavenging effects compared to PBT2. The results suggested that 7a and 7b are promising lead compounds for the development of a new therapy for AD.
authors.affiliation: School of Pharmacy, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Chin-Lan
authors.initials: CL
authors.lastname: Fu
authors.affiliation: School of Pharmacy, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Li-Shin
authors.initials: LS
authors.lastname: Hsu
authors.affiliation: Laboratories of Molecular Neurobiology, Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
authors.forename: Yung-Feng
authors.initials: YF
authors.lastname: Liao
authors.affiliation: School of Pharmacy, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Ming-Kuan
authors.initials: MK
authors.lastname: Hu
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D002614:Chelating Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D007464:Clioquinol / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D003300:Copper / Q000009:adverse effects; D006912:Hydroxyquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D066263:Protein Aggregation, Pathological / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D015032:Zinc / Q000009:adverse effects
chemical_list: D016229:Amyloid beta-Peptides; D002614:Chelating Agents; D006912:Hydroxyquinolines; C531955:PBT2 compound; D003300:Copper; D007464:Clioquinol; D015032:Zinc
keywords: Alzheimer's disease; Amyloid-β aggregations; Multi-target modulators; Reactive oxygen species