A small bifunctional chelator that modulates Aβ42 aggregation

Zhang, Chaofeng; Gomes, Luiza M. F.; Zhang, Tonglu; Storr, Tim

doi:10.1139/cjc-2017-0623

Cited by 9 publications

(10 citation statements)

References 49 publications

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“…Multifunctional molecules based on p-I stilbene (pISTIB) can chelate Cu(II) to regulate Cu(II)-induced Aβ aggregation [185][186][187][188][189][190][191][192][193][194]. Even though the exact role of triazole has not yet been elucidated, triazole-based chemicals have been developed having a quinoline ring and a phenol [195][196][197]. Multifunctional molecules affected metal-free Aβ aggregation, and others reduced Cu(II)-induced Aβ aggregation when selegiline, aurone, and chromone were conjugated [198][199][200].…”

Section: Regulators Of Cu(i/ii)mentioning

confidence: 99%

Redox-Active Metal Ions and Amyloid-Degrading Enzymes in Alzheimer’s Disease

Kim

Lee

2021

IJMS

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Redox-active metal ions, Cu(I/II) and Fe(II/III), are essential biological molecules for the normal functioning of the brain, including oxidative metabolism, synaptic plasticity, myelination, and generation of neurotransmitters. Dyshomeostasis of these redox-active metal ions in the brain could cause Alzheimer’s disease (AD). Thus, regulating the levels of Cu(I/II) and Fe(II/III) is necessary for normal brain function. To control the amounts of metal ions in the brain and understand the involvement of Cu(I/II) and Fe(II/III) in the pathogenesis of AD, many chemical agents have been developed. In addition, since toxic aggregates of amyloid-β (Aβ) have been proposed as one of the major causes of the disease, the mechanism of clearing Aβ is also required to be investigated to reveal the etiology of AD clearly. Multiple metalloenzymes (e.g., neprilysin, insulin-degrading enzyme, and ADAM10) have been reported to have an important role in the degradation of Aβ in the brain. These amyloid degrading enzymes (ADE) could interact with redox-active metal ions and affect the pathogenesis of AD. In this review, we introduce and summarize the roles, distributions, and transportations of Cu(I/II) and Fe(II/III), along with previously invented chelators, and the structures and functions of ADE in the brain, as well as their interrelationships.

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Section: Regulators Of Cu(i/ii)mentioning

confidence: 99%

Redox-Active Metal Ions and Amyloid-Degrading Enzymes in Alzheimer’s Disease

Kim

Lee

2021

IJMS

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“…The first drug with metal-binding ability used in the therapy of AD was clioquinol [158], which unfortunately is unsuitable for long-term use due to several side effects [159]. Its successors are other metal-binding drugs and their derivatives: triazole [160][161][162][163][164][165] deferiprone [166][167][168], 8-hydroxyquinoline [158,[169][170][171][172][173], cyclam [174][175][176][177][178], thioflavin T [179][180][181][182][183], p-I-stilbene [184,185], chalcone [163,164], resveratrol [186,187], flavone [188,189], donepezil [190,191], tacrine [192,193], and dopamine [194]. Nevertheless, chelating agents that remove metal overload from the cell have proven to be only partially effective in the treatment of neurodegeneration [195].…”

Section: Therapy For Metal-related Pathologiesmentioning

confidence: 99%

Metals and Metal-Nanoparticles in Human Pathologies: From Exposure to Therapy

et al. 2021

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An increasing number of pathologies correlates with both toxic and essential metal ions dyshomeostasis. Next to known genetic disorders (e.g., Wilson’s Disease and β-Thalassemia) other pathological states such as neurodegeneration and diabetes are characterized by an imbalance of essential metal ions. Metal ions can enter the human body from the surrounding environment in the form of free metal ions or metal-nanoparticles, and successively translocate to different tissues, where they are accumulated and develop distinct pathologies. There are no characteristic symptoms of metal intoxication, and the exact diagnosis is still difficult. In this review, we present metal-related pathologies with the most common onsets, biomarkers of metal intoxication, and proper techniques of metal qualitative and quantitative analysis. We discuss the possible role of drugs with metal-chelating ability in metal dyshomeostasis, and present recent advances in therapies of metal-related diseases.

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“…Metal-chelating compounds (MCCs) were designed through the incorporation strategy by merging chemical structures of Aβ binding moiety with a metal-chelating ligand. [30][31][32][33] The synthetic route of MCCs starts with oxidative cyclization of 2aminothiophenol and 6-methylnicotinaldehyde, followed by Nbromosuccinimide (NBS) bromination for further conjugation with the multidentate ligands (Scheme 1). The MCCs were then chelated with 64 CuCl2 in 0.1 M NH4OAc (pH 5.5) and the 64 Cucomplexes were used without further purification (radiochemical yield > 95%).…”

Section: Design and Synthesis Of Metal-chelating Compoundsmentioning

confidence: 99%

Neutral Metal-Chelating Compounds with High 64Cu Affinity for PET Imaging Applications in Alzheimer’s Disease

Mirica

Huang²,

Huynh³

et al. 2021

Preprint

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<div> Positron emission tomography (PET), which uses positron-emitting radionuclides to visualize and measure processes in the human body, is a useful noninvasive diagnostic tool for Alzheimer’s disease (AD). The development of longer-lived radiolabeled compounds is essential for further expanding the use of PET imaging in healthcare, and diagnostic agents employing longer-lived radionuclides such as 64Cu (t1/2 = 12.7 h, β+ = 17%, β- = 39%, EC = 43%, Emax = 0.656 MeV) are capable of accomplishing this. One limitation of 64Cu PET agents is that they could release free radioactive Cu ions from the metal complexes, which decreases the signal to noise ratio and accuracy of imaging. Herein, a series of 1,4,7-triazacyclononane (TACN) and 2,11-diaza[3.3]-(2,6)pyridinophane (N4)-based <a>metal-chelating compounds with pyridine arms were designed and synthesized by incorporating Aβ-interacting fragments into metal-binding ligands, which allows for excellent Cu chelation without diminishing their Aβ-binding affinity. </a>The crystal structures of the corresponding Cu complexes confirmed the pyridine N atoms are involved in binding to Cu. Radiolabeling and autoradiopraphy studies show that <a>the compounds efficiently chelate 64Cu, and the resulting complexes exhibit specific binding to the amyloid plaques in the AD mouse brain sections vs. WT controls.</a> </div>

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A small bifunctional chelator that modulates Aβ₄₂ aggregation

Cited by 9 publications

References 49 publications

Redox-Active Metal Ions and Amyloid-Degrading Enzymes in Alzheimer’s Disease

Redox-Active Metal Ions and Amyloid-Degrading Enzymes in Alzheimer’s Disease

Metals and Metal-Nanoparticles in Human Pathologies: From Exposure to Therapy

Neutral Metal-Chelating Compounds with High 64Cu Affinity for PET Imaging Applications in Alzheimer’s Disease

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