8-Hydroxyquinoline Schiff-base compounds as antioxidants and modulators of copper-mediated Aβ peptide aggregation

Gomes, Luiza M. F.; Vieira, Rafael P.; Jones, Michael R.; Wang, Michael C. P.; Dyrager, Christine; Souza-Fagundes, Elaine M.; Silva, Jéferson G. Da; Storr, Tim; Beraldo, Heloísa

doi:10.1016/j.jinorgbio.2014.04.011

Cited by 78 publications

(41 citation statements)

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“…Currently, several types of inhibitors that target amyloid aggregation are under development, including small molecule inhibitors, peptides, nanoparticles, antibodies, and proteins . Among them, peptides and peptidomimetics have been extensively studied for their specific interactions with Aβ .…”

Section: Introductionmentioning

confidence: 99%

Design of nonapeptide LVFFARKHH: A bifunctional agent against Cu²⁺‐mediated amyloid β‐protein aggregation and cytotoxicity

Zhang

Dong

et al. 2018

J of Molecular Recognition

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Dysfunctional accumulation of amyloid β-protein (Aβ) mediated by Cu exhibits higher neurotoxicity and accelerates the progress of Alzheimer's disease, so inhibition of Cu -mediated Aβ aggregation and cytotoxicity has been considered as a therapeutic strategy for the disease. Herein, a nonapeptide was designed by linking HH to the C-terminus of a peptide inhibitor of Aβ aggregation, LVFFARK (LK7). We found that the nonapeptide, LK7-HH, possessed dual functionality, including enhanced inhibition capability on Aβ aggregation as compared to LK7, and chelating Cu with a dissociation constant of 5.50 μM. This enabled LK7-HH to arrest the generation of reactive oxygen species catalyzed by Cu or Cu -Aβ complex, and to inhibit Cu -induced Aβ aggregation. Moreover, in contrast with the cytotoxicity of LK7 aggregates, LK7-HH was biocompatible because HH conjugation made its aggregation behavior different from LK7. Thus, LK7-HH efficiently suppressed Cu -mediated Aβ aggregation and cytotoxicity. An equimolar concentration of LK7-HH increased cell viability from 50% to 90% when treating Aβ -Cu complexes. The results provided insights into the roles of HH in enhancing the inhibition of Aβ and Cu -induced Aβ aggregations, in eliminating Cu -induced cytotoxicities by arresting generation of reactive oxygen species, and in making the peptide biocompatible. Therefore, this work would contribute to the design of potent peptide-based inhibitors of Cu -mediated Aβ aggregation and cytotoxicity.

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Section: Introductionmentioning

confidence: 99%

Design of nonapeptide LVFFARKHH: A bifunctional agent against Cu²⁺‐mediated amyloid β‐protein aggregation and cytotoxicity

Zhang

Dong

et al. 2018

J of Molecular Recognition

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“…As Cu II promotes Aβ aggregation, chelation therapy could be utilised to inhibit aggregation (Greenough et al, ). We examined the effect of the selected nicotinoyl hydrazones, PCNH, 8‐OH‐QNH, SNH2, SNH3, SNH5, SNH6, SNH8, and PrNH1, on the inhibition of Cu II ‐mediated Aβ 1–40 aggregation (Gomes et al, ; Figure c). The well‐characterised chelators, DTPA, Dp44mT, SBH, and SIH, were controls.…”

Section: Resultsmentioning

confidence: 99%

“…A well‐characterised turbidimetric assay was utilised to examine the ability of the nicotinoyl hydrazones to inhibit Cu(II)‐mediated aggregation of Aβ 1–40 (Gomes et al, ; Jones et al, ). Based on data from previous studies assessing Cu(II)‐mediated Aβ aggregation (Gomes et al, ; Jones et al, ), a sample size of 12 biological replicates was determined using a priori power analysis (G*Power 3.1). This generated >80% statistical power to detect at least 20% difference in mean with an effect size of 1.25 and SD of 0.16.…”

Section: Methodsmentioning

confidence: 99%

Novel multifunctional iron chelators of the aroyl nicotinoyl hydrazone class that markedly enhance cellular NAD⁺/NADH ratios

Palanimuthu

Braidy

et al. 2020

British J Pharmacology

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Background and Purpose: Alzheimer's disease (AD) is a multifactorial condition leading to cognitive decline and represents a major global health challenge in ageing populations. The lack of effective AD therapeutics led us to develop multifunctional nicotinoyl hydrazones to target several pathological characteristics of AD.Experimental Approach: We synthesised 20 novel multifunctional agents based on the nicotinoyl hydrazone scaffold, which acts as a metal chelator and a lipophilic delivery vehicle, donating a NAD + precursor to cells, to target metal dyshomeostasis, oxidative stress, β-amyloid (Aβ) aggregation, and a decrease in the NAD + /NADH ratio.Key Results: The most promising compound, 6-methoxysalicylaldehyde nicotinoyl hydrazone (SNH6), demonstrated low cytotoxicity, potent iron (Fe)-chelation efficacy, significant inhibition of copper-mediated Aβ aggregation, oxidative stress alleviation, effective donation of NAD + to NAD-dependent metabolic processes (PARP and sirtuin activity) and enhanced cellular NAD + /NADH ratios, as well as significantly increased median Caenorhabditis elegans lifespan (to 1.46-fold of the control); partly decreased BACE1 expression, resulting in significantly lower soluble amyloid precursor protein-β (sAPPβ) and Aβ 1-40 levels; and favourable blood-brain barrierpermeation properties. Structure-activity relationships demonstrated that the ability of these nicotinoyl hydrazones to increase NAD + was dependent on the electronwithdrawing or electron-donating substituents on the aldehyde-or ketone-derived moiety. Aldehyde-derived hydrazones containing the ONO donor set and electrondonating groups were required for NAD + donation and low cytotoxicity. Conclusions and Implications:The nicotinoyl hydrazones, particularly SNH6, have the potential to act as multifunctional therapeutic agents and delivery vehicles for NAD + precursors for AD treatment.Abbreviations: 59 Fe2-Tf, iron-59 labelled diferric transferrin; 8-OH-QNH, 8-hydroxy-2-quinolinecarboxaldehyde nicotinoyl hydrazone; Aβ, β-amyloid; AcNH1, 4 0 -fluoro-2 0 -hydroxyacetophenone nicotinoyl hydrazone; AcNH2, 5 0 -bromo-2 0 -hydroxyacetophenone nicotinoyl hydrazone; AD, Alzheimer's disease; APP, amyloid precursor protein; BBB, blood-brain barrier; DTPA, diethylenetriaminepentaacetic acid; InNH1, 7-hydroxy-1-indanone nicotinoyl hydrazone; InNH2, 7-hydroxy-6-methyl-1-indanone nicotinoyl hydrazone; InNH3, 4-bromo-7-hydroxy-1-indanone nicotinoyl hydrazone; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NNH, 2-hydroxy-1-naphthaldehyde nicotinoyl hydrazone; PAMPA-BBB, parallel artificial membrane permeability assay of the blood-brain barrier; PCNH, 2-pyridinecarboxaldehyde nicotinoyl hydrazone; PNH, pyridoxal nicotinoyl hydrazone; PrNH1, 5 0 -bromo-2 0

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“…Although we did not test the antioxidant properties of L1, we expect the phenol moiety to exhibit ROS quenching effects as reported for similar derivatives. [43][44][45] The interaction of the ligand with Cu 2+ was probed using UV-vis spectroscopy. Upon addition of CuCl 2 to a solution of ligand, decreased intensity and shifts of the optical band at ca.…”

Section: Resultsmentioning

confidence: 99%

A small bifunctional chelator that modulates Aβ₄₂ aggregation

et al. 2018

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Multifunctional compounds that can modulate amyloid-␤ (A␤) aggregation and interact with metal ions hold considerable promise as therapeutic agents for Alzheimer's disease (AD). Using the copper-catalyzed azide-alkyne cycloaddition reaction, a novel bifunctional chelator 2-(1-(4-(dimethylamino)benzyl)-1H-1,2,3-triazol-4-yl)phenol (L1) was synthesized. L1 contains a bidentate metal-binding unit and a pendant dimethylamino moiety. The product was characterized by 1 H NMR, 13 C NMR, and MS. The metal-binding properties of L1 were probed by UV-vis spectroscopy to determine Cu:L stoichiometry. L1 was determined to limit A␤ aggregation at 48 h via a ThT assay. In addition, L1 complies with Lipinski's rules and calculated logBB values for potential drug likeness and BBB permeability. These results suggest that L1 is a suitable candidate for further study as a multifunctional compound to treat AD.Résumé : Les composés multifonctionnels ayant la capacité de moduler l'agrégation de la ␤-amyloïde (A␤) et d'interagir avec les ions métalliques sont des agents thérapeutiques fort prometteurs comme contre la maladie d'Alzheimer. Nous avons synthétisé, par réaction de cycloaddition catalysée par le cuivre entre un azoture et un alcyne, un nouveau chélateur bifonctionnel, le 2-(1-(4-(diméthylamino)benzyl)-1H-1,2,3-triazol-4-yl)phénol (L1). Le composé L1 comporte une unité bidentate se liant à l'atome métallique et un appendice portant un groupe diméthylamino. Nous avons caractérisé le produit par RMN 1 H, RMN 13 C et spectroscopie de masse (MS). Nous avons aussi étudié les propriétés de liaison à l'atome métallique du composé L1 par spectroscopie UV-vis afin de déterminer le rapport stoechiométrique Cu:L. À l'aide d'un essai à la thioflavine T (ThT), nous avons déterminé que le composé L1 limitait l'agrégation de l'Ab après 48 h. Par ailleurs, le composé L1 répond aux règles de Lipinski en ce qui concerne la pharmacopotentialité, et les valeurs calculées de son logBB sont compatibles avec la pénétration de la barrière hématoencéphalique. Ces résultats permettent de croire que le composé L1 vaut la peine d'être étudié davantage comme composé multif onctionnel dans le traitement de la maladie d'Alzheimer. [Traduit par la Rédaction] Mots-clés : ␤-amyloïde, maladie d'Alzheimer, chimie clic, ions de cuivre.

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8-Hydroxyquinoline Schiff-base compounds as antioxidants and modulators of copper-mediated Aβ peptide aggregation

Abstract: One of the hallmarks of Alzheimer's disease (AD) in the brain are amyloid- (A) plaques, and metal ions such as copper(II) and zinc(II) have been shown to play a role in the aggregation and toxicity of the A peptide, the major constituent of these

Cited by 78 publications

References 90 publications

Design of nonapeptide LVFFARKHH: A bifunctional agent against Cu²⁺‐mediated amyloid β‐protein aggregation and cytotoxicity

Design of nonapeptide LVFFARKHH: A bifunctional agent against Cu²⁺‐mediated amyloid β‐protein aggregation and cytotoxicity

Novel multifunctional iron chelators of the aroyl nicotinoyl hydrazone class that markedly enhance cellular NAD⁺/NADH ratios

A small bifunctional chelator that modulates Aβ₄₂ aggregation

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8-Hydroxyquinoline Schiff-base compounds as antioxidants and modulators of copper-mediated Aβ peptide aggregation

Abstract: One of the hallmarks of Alzheimer's disease (AD) in the brain are amyloid- (A) plaques, and metal ions such as copper(II) and zinc(II) have been shown to play a role in the aggregation and toxicity of the A peptide, the major constituent of these

Cited by 78 publications

References 90 publications

Design of nonapeptide LVFFARKHH: A bifunctional agent against Cu2+‐mediated amyloid β‐protein aggregation and cytotoxicity

Design of nonapeptide LVFFARKHH: A bifunctional agent against Cu2+‐mediated amyloid β‐protein aggregation and cytotoxicity

Novel multifunctional iron chelators of the aroyl nicotinoyl hydrazone class that markedly enhance cellular NAD+/NADH ratios

A small bifunctional chelator that modulates Aβ42 aggregation

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Design of nonapeptide LVFFARKHH: A bifunctional agent against Cu²⁺‐mediated amyloid β‐protein aggregation and cytotoxicity

Design of nonapeptide LVFFARKHH: A bifunctional agent against Cu²⁺‐mediated amyloid β‐protein aggregation and cytotoxicity

Novel multifunctional iron chelators of the aroyl nicotinoyl hydrazone class that markedly enhance cellular NAD⁺/NADH ratios

A small bifunctional chelator that modulates Aβ₄₂ aggregation