Importance of the Dimethylamino Functionality on a Multifunctional Framework for Regulating Metals, Amyloid-β, and Oxidative Stress in Alzheimer’s Disease

Abstract

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.

Structural and Mechanistic Insights into Development of Chemical Tools to Control Individual and Inter‐Related Pathological Features in Alzheimer's Disease

“…The scavenging ability of the different compounds against free radicals was measured by the Trolox (vitamin E analogue) equivalent antioxidant capacity (TEAC) assay, which can evaluate compounds’ capability of quenching ABTS cation radicals [ABTS .+ ; ABTS = 2,2′‐azino‐bis(3‐ethylbenzothiazoline‐6‐sulfonic acid)] in both an organic solution (i.e., EtOH) and a biologically relevant environment (i.e., cell lysates) –. As shown in Figure b, the TEAC values of L2‐b1 and L2‐b2 were determined (0.8 ± 0.1 and 1.9 ± 0.1 in EtOH; 0.7 ± 0.1 and 1.1 ± 0.1 in M17 lysates, respectively).…”

Advances in Multi-Functional Ligands and the Need for Metal-Related Pharmacology for the Management of Alzheimer Disease

“…The fluorescence imaging probes detected the presence of soluble Aβ form in in vivo experiment ( Zhang et al, 2013 ). Antiamyloidogenic property of aminoquinoline derivatives in both the absence and presence of metal ions was investigated, revealed that dimethyl amino group is the structural element essential for giving antiamyloidogenic activity ( Derrick et al, 2016 ). Ferulic acid is a small phenolic molecule possessing strong antioxidant properties and inhibiting Aβ aggregation ( Bramanti et al, 2013 ).…”

“…Quinolone inspired molecules with a metal-binding component and antioxidant activity were designed by many research groups. Compounds exhibited antioxidant potential through binding metal ions, quenching radical ions via phenolic group thus preventing redox cycling ( Braymer et al, 2011 ; Savelieff et al, 2014 ; Derrick et al, 2016 ). The prevention of generation of free radicals is important since it leads to oxidative damage which ultimately causes neuronal cells death.…”

Synthesis and Evaluation of New Cyclodextrin Derivatives as Amyloid‐β Aggregation Inhibitors

“…All of the PET imaging probes in clinical trials contain a monomethylamino or dimethylamino group that confers binding specificity to Aβ aggregates . Moreover, a recent study has reported that the blood‐brain barrier (BBB)‐permeable chemical reagent, N,N‐dimethyl‐p‐phenylenediamine (DMPD) can interact with both metal‐free Aβ and metal−Aβ and alter their aggregation pathways . Also, some authors have reported that chemical structural moieties such as the dimethylamino functionality are essential to tune the reactivity of small bifunctional molecules toward metal‐induced Aβ aggregation and neurotoxicity …”