Redox Properties of Small Molecules Essential for Multiple Reactivities with Pathological Factors in Alzheimer's Disease

Kim, Mingeun; Lim, Mi Hee

doi:10.1002/bkcs.12372

Cited by 11 publications

(7 citation statements)

References 89 publications

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“…The redox activity of small molecules is critical for controlling multiple pathological features of AD, including free radicals, metal-free Ab, and metal-Ab. 47,[52][53][54][55] In particular, redox properties of small molecules are connected with their antioxidant ability. 56 Thus, the redox potential of avonoids were rst computed following the previously reported density functional theory (DFT) calculation.…”

Section: Redox Potentials and Scavenging Free Radicalsmentioning

confidence: 99%

Designing multi-target-directed flavonoids: a strategic approach to Alzheimer's disease

Park¹,

Kim²,

Lin³

et al. 2023

Chem. Sci.

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Section: Redox Potentials and Scavenging Free Radicalsmentioning

confidence: 99%

Designing multi-target-directed flavonoids: a strategic approach to Alzheimer's disease

Park¹,

Kim²,

Lin³

et al. 2023

Chem. Sci.

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“… 227 Molecular architecture has been fine tuned to generate Aβ, metal and ROS targeting small molecules. 228 Few combination therapies and dual targeting molecules were developed with better therapeutic benefits. We propose multifunctional small molecules that target multiple disease targets as potential future drug candidates for AD ( Fig.…”

Section: Therapeutic Strategiesmentioning

confidence: 99%

Multipronged diagnostic and therapeutic strategies for Alzheimer's disease

Ramesh

Govindaraju

2022

Chem. Sci.

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“…20 Fe(II/III) and Cu(I/II) could catalytically convert H 2 O 2 to •OH through Fenton chemistry and Fenton-like reactions, respectively. 7,15,20,21 To control the presence and production of ROS, our group has focused on developing small molecules with antioxidant activity and the ability to disrupt the redox cycling of Cu(I/II) or Cu(I/II)- 57 which is stabilized by electron-donating amino and dimethylamino groups. 3,4 Therefore, these molecules could scavenge free organic radicals to a degree similar to that of Trolox.…”

Section: Scavenging Rosmentioning

confidence: 99%

“…Fe(II/III) and Cu(I/II) could catalytically convert H 2 O 2 to •OH through Fenton chemistry and Fenton-like reactions, respectively. ,,, To control the presence and production of ROS, our group has focused on developing small molecules with antioxidant activity and the ability to disrupt the redox cycling of Cu(I/II) or Cu(I/II)-bound Aβ by geometrically controlling the metal center. The preexisting ROS can be effectively quenched by antioxidants designed to possess appropriate redox potentials. , For example, PPD and DMPD (Figure c) easily undergo one-electron oxidation [ E 1/2 = −40 and −119 mV versus Ag/Ag(I) in CH 3 CN with 1% v/v DMSO, respectively], which is stabilized by electron-donating amino and dimethylamino groups. , Therefore, these molecules could scavenge free organic radicals to a degree similar to that of Trolox. In parallel, Cu(I/II)-mediated Fenton-like reactions involved in ROS formation (Figure b) can be prevented by governing the geometric accommodation on the copper center.…”

Section: Mechanistic Investigations For the Reactivities Of Small Mol...mentioning

confidence: 99%

Mechanistic Insight into the Design of Chemical Tools to Control Multiple Pathogenic Features in Alzheimer’s Disease

Han

Lim

2021

Acc. Chem. Res.

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Conspectus Alzheimer’s disease (AD) is the most common form of dementia and is characterized by memory loss and cognitive decline. Approximately 50 million people worldwide are suffering from AD and related dementias. Very recently, the first new drug targeting amyloid-β (Aβ) aggregates has been approved by the United States Food and Drug Administration, but its efficacy against AD is still debatable. Other available treatments temporarily relieve the symptoms of AD. The difficulty in discovering effective therapeutics for AD originates from its complicated nature, which results from the interrelated pathogenic pathways led by multiple factors. Therefore, to develop potent disease-modifying drugs, multiple pathological features found in AD should be fully elucidated. Our laboratory has been designing small molecules as chemical tools to investigate the individual and interrelated pathologies triggered by four pathogenic elements found in the AD-affected brain: metal-free Aβ, metal-bound Aβ, reactive oxygen species (ROS), and acetylcholinesterase (AChE). Aβ peptides are partially folded and aggregate into oligomers, protofibrils, and fibrils. Aβ aggregates are considered to be neurotoxic, causing membrane disruption, aberrant cellular signaling, and organelle dysfunction. In addition, highly concentrated metal ions accumulate in senile plaques mainly composed of Aβ aggregates, which indicates that metal ions can directly interact with Aβ. Metal binding to Aβ affects the aggregation and conformation of the peptide. Moreover, the impaired homeostasis of redox-active Fe(II/III) and Cu(I/II) induces the overproduction of ROS through Fenton chemistry and Fenton-like reactions, respectively. Dysregulated ROS prompt oxidative-stress-damaging biological components such as lipids, proteins, and nucleic acids and, consequently, lead to neuronal death. Finally, the loss of cholinergic transmission mediated by the neurotransmitter acetylcholine (ACh) contributes to cognitive deficits observed in AD. In this Account, we illustrate the design principles for small-molecule-based chemical tools with reactivities against metal-free Aβ, metal-bound Aβ, ROS, and AChE. More importantly, mechanistic details at the molecular level are highlighted with some examples of chemical tools that were developed by our group. The aggregation of metal-free Aβ can be modulated by modifying amino acid residues responsible for self-assembling Aβ or disassembling preformed fibrils. To alter the aggregation and cytotoxicity profiles of metal-bound Aβ, ternary complexation, metal chelation, and modifications onto metal-binding residues can be effective tactics. The presence and production of ROS are able to be controlled by small molecules with antioxidant and metal-binding properties. Finally, inhibiting substrate access or substrate binding at the active site of AChE can diminish its activity, which restores the levels of ACh. Overall, our rational approaches demonstrate the feasibility of developing small molecules as chemical tools that can ta...

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Redox Properties of Small Molecules Essential for Multiple Reactivities with Pathological Factors in Alzheimer's Disease

Cited by 11 publications

References 89 publications

Designing multi-target-directed flavonoids: a strategic approach to Alzheimer's disease

Designing multi-target-directed flavonoids: a strategic approach to Alzheimer's disease

Multipronged diagnostic and therapeutic strategies for Alzheimer's disease

Mechanistic Insight into the Design of Chemical Tools to Control Multiple Pathogenic Features in Alzheimer’s Disease

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