Regulatory Activities of Dopamine and Its Derivatives toward Metal-Free and Metal-Induced Amyloid‑β Aggregation, Oxidative Stress, and Inflammation in Alzheimer’s Disease

A catecholamine neurotransmitter, dopamine (<b>DA</b>), is suggested to be linked to the pathology of dementia; however, the involvement of <b>DA</b> and its structural analogues in the pathogenesis of Alzheimer’s disease (AD), the most common form of dementia, composed of multiple pathogenic factors has not been clear. Herein, we report that <b>DA</b> and its rationally designed structural derivatives (<b>1</b>–<b>6</b>) based on <b>DA</b>’s oxidative transformation are able to modulate multiple pathological elements found in AD [i.e., metal ions, metal-free amyloid-β (Aβ), metal-bound Aβ (metal–Aβ), and reactive oxygen species (ROS)], with demonstration of detailed molecular-level mechanisms. Our multidisciplinary studies validate that the protective effects of <b>DA</b> and its derivatives on Aβ aggregation and Aβ-mediated toxicity are induced by their oxidative transformation with concomitant ROS generation under aerobic conditions. In particular, <b>DA</b> and the derivatives (i.e., <b>3</b> and <b>4</b>) show their noticeable anti-amyloidogenic ability toward metal-free Aβ and/or metal–Aβ, verified to occur via their oxidative transformation that facilitates Aβ oxidation. Moreover, in primary pan-microglial marker (CD11b)-positive cells, the major producers of inflammatory mediators in the brain, <b>DA</b> and its derivatives significantly diminish inflammation and oxidative stress triggered by lipopolysaccharides and Aβ through the reduced induction of inflammatory mediators as well as upregulated expression of heme oxygenase-1, the enzyme responsible for production of antioxidants. Collectively, we illuminate how <b>DA</b> and its derivatives could prevent multiple pathological features found in AD. The overall studies could advance our understanding regarding distinct roles of neurotransmitters in AD and identify key interactions for alleviation of AD pathology

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 (<b>ML</b>) 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 (<b>AQ1</b>–<b>4</b>, <b>AQP1</b>–<b>4</b>, and <b>AQDA1</b>–<b>3</b>) based on <b>ML</b>’s framework, prepared to gain a structure–reactivity understanding of <b>ML</b>’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 <b>ML</b> in both the absence and presence of metal ions. Two-dimensional NMR studies indicate that structural variations of <b>ML</b> 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 <b>ML</b> 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

Terminal and Internal Olefin Epoxidation with Cobalt(II) as the Catalyst: Evidence for an Active Oxidant Co^II–Acylperoxo Species

A simple catalytic system that uses commercially available cobalt­(II) perchlorate as the catalyst and 3-chloroperoxybenzoic acid as the oxidant was found to be very effective in the epoxidation of a variety of olefins with high product selectivity under mild experimental conditions. More challenging targets such as terminal aliphatic olefins were also efficiently and selectively oxidized to the corresponding epoxides. This catalytic system features a nearly nonradical-type and highly stereospecific epoxidation of aliphatic olefin, fast conversion, and high yields. Olefin epoxidation by this catalytic system is proposed to involve a new reactive Co^II–OOC­(O)­R species, based on evidence from H₂¹⁸O-exchange experiments, the use of peroxyphenylacetic acid as a mechanistic probe, reactivity and Hammett studies, EPR, and ESI-mass spectrometric investigation. However, the O–O bond of a Co^II–acylperoxo intermediate (Co^II–OOC­(O)­R) was found to be cleaved both heterolytically and homolytically if there is no substrate

Mechanistic Insights into Tunable Metal-Mediated Hydrolysis of Amyloid‑β Peptides

An amyloidogenic peptide, amyloid-β (Aβ), has been implicated as a contributor to the neurotoxicity of Alzheimer’s disease (AD) that continues to present a major socioeconomic burden for our society. Recently, the use of metal complexes capable of cleaving peptides has arisen as an efficient tactic for amyloid management; unfortunately, little has been reported to pursue this strategy. Herein, we report a novel approach to validate the hydrolytic cleavage of divalent metal complexes toward two major isoforms of Aβ (Aβ₄₀ and Aβ₄₂) and tune their proteolytic activity based on the choice of metal centers (M = Co, Ni, Cu, and Zn) which could be correlated to their anti-amyloidogenic properties. Such metal-dependent tunability was facilitated employing a tetra-<i>N</i>-methylated cyclam (TMC) ligand that imparts unique geometric and stereochemical control, which has not been available in previous systems. Co­(II)­(TMC) was identified to noticeably cleave Aβ peptides and control their aggregation, reporting the first Co­(II) complex for such reactivities to the best of our knowledge. Through detailed mechanistic investigations by biochemical, spectroscopic, mass spectrometric, and computational studies, the critical importance of the coordination environment and acidity of the aqua-bound complexes in promoting amide hydrolysis was verified. The biological applicability of Co­(II)­(TMC) was also illustrated via its potential blood-brain barrier permeability, relatively low cytotoxicity, regulatory capability against toxicity induced by both Aβ₄₀ and Aβ₄₂ in living cells, proteolytic activity with Aβ peptides under biologically relevant conditions, and inertness toward cleavage of structured proteins. Overall, our approaches and findings on reactivities of divalent metal complexes toward Aβ, along with the mechanistic insights, demonstrate the feasibility of utilizing such metal complexes for amyloid control