Importance of the Dimethylamino Functionality on a Multifunctional Framework for Regulating Metals, Amyloid-β, and Oxidative Stress in Alzheimer's Disease.
The complex and multifaceted pathology of Alzheimer's disease (AD) continues to present a formidable challenge to the establishment of long-term treatment strategies. Multifunctional compounds able to modulate the reactivities of various pathological features, such as amyloid-β (Aβ) aggregation, metal ion dyshomeostasis, and oxidative stress, have emerged as a useful tactic. Recently, an incorporation approach to the rational design of multipurpose small molecules has been validated through the production of a multifunctional ligand (ML) as a potential chemical tool for AD. In order to further the development of more diverse and improved multifunctional reagents, essential pharmacophores must be identified. Herein, we report a series of aminoquinoline derivatives (AQ1-4, AQP1-4, and AQDA1-3) based on ML's framework, prepared to gain a structure-reactivity understanding of ML's multifunctionality in addition to tuning its metal binding affinity. Our structure-reactivity investigations have implicated the dimethylamino group as a key component for supplying the antiamyloidogenic characteristics of ML in both the absence and presence of metal ions. Two-dimensional NMR studies indicate that structural variations of ML could tune its interaction sites along the Aβ sequence. In addition, mass spectrometric analyses suggest that the ability of our aminoquinoline derivatives to regulate metal-induced Aβ aggregation may be influenced by their metal binding properties. Moreover, structural modifications to ML were also observed to noticeably change its metal binding affinities and metal-to-ligand stoichiometries that were shown to be linked to their antiamyloidogenic and antioxidant activities. Overall, our studies provide new insights into rational design strategies for multifunctional ligands directed at regulating metal ions, Aβ, and oxidative stress in AD and could advance the development of improved next-generation multifunctional reagents.
Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST) , Ulsan 44919, Republic of Korea.
Jeffrey S
JS
Derrick
Richard A
RA
Kerr
Kyle J
KJ
Korshavn
Michael J
MJ
McLane
Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST) , Ulsan 44919, Republic of Korea.
Juhye
J
Kang
Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST) , Ulsan 44919, Republic of Korea.
Eunju
E
Nam
Ayyalusamy
A
Ramamoorthy
Brandon T
BT
Ruotolo
Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST) , Ulsan 44919, Republic of Korea.
Mi Hee
MH
Lim
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D000634:Aminoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D045744:Cell Line, Tumor; D003300:Copper / Q000737:chemistry; D004123:Dimethylamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000737:chemistry*; D055503:Protein Multimerization; D017382:Reactive Oxygen Species / Q000737:chemistry; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry
D000634:Aminoquinolines; D016229:Amyloid beta-Peptides; D000975:Antioxidants; D004123:Dimethylamines; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D003300:Copper; D015032:Zinc