No abstract

An Fe corrole is shown to bind to the amyloid-beta peptide and limit reactive oxygen species generation and peptide aggregation of relevance to Alzheimer's disease.

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

Photoactivation of a series of Ru(ii) polypyridyl complexes leads to ligand exchange and modulation of amyloid-beta peptide aggregation of relevance to Alzheimer's disease.

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.

Alzheimer's disease (AD) is the most common form of dementia, leading to loss of cognition, and eventually death. The disease is characterized by the formation of extracellular aggregates of the amyloid-beta (Aβ) peptide and neurofibrillary tangles of tau protein inside cells, and oxidative stress. In this study, we investigate a series of Ru(III) complexes (Ru-N) derived from NAMI-A in which the imidazole ligand has been substituted for pyridine derivatives, as potential therapeutics for AD. The ability of the RuN series to bind to Aβ was evaluated by NMR and ESI-MS, and their influence on the Aβ peptide aggregation process was investigated via electrophoresis gel/western blot, TEM, turbidity, and Bradford assays. The complexes were shown to bind covalently to the Aβ peptide, likely via a His residue. Upon binding, the complexes promote the formation of soluble high molecular weight aggregates, in comparison to peptide precipitation for peptide alone. In addition, TEM analysis supports both amorphous and fibrillar aggregate morphology for RuN treatments, while only large amorphous aggregates are observed for peptide alone. Overall, our results show that the RuN complexes modulate Aβ peptide aggregation, however, the change in the size of the pyridine ligand does not substantially alter the Aβ aggregation process.

In cells and organisms, metal complexes can be specifically designed to interact with biomolecules and accordingly alter important biological processes. These interactions have been widely explored for targeting specific biological functions and diseases. In fact, several studies have demonstrated that inorganic chemistry offers significant diversity and versatility for the preparation of highly potent protein modulators (e.g., inhibitors). Moreover, both coordination and organometallic complexes featuring favorable chemico‐physical properties (e.g., luminescence) have proven to be well suited to image proteins and peptides in living cells by various methods. An inherent advantage of metal complexes is the accessibility of multiple oxidation states, and overall charge and geometries, which makes them attractive from the point of view of chemical design. However, these properties can become a disadvantage if not controlled and fine‐tuned in the biological application. In this review, we generally discuss the use of metal compounds, targeting proteins and/or peptides, in medicinal chemistry and chemical biology, and then focus on representative recent examples and applications. Furthermore, we highlight future challenges and attractive perspectives in the field, which may stimulate research and define new frontiers in bioinorganic chemistry.

Resumo Objetivou-se avaliar os impactos da COVID-19 no rastreamento do câncer de mama no Brasil. Coletaram-se dados do Sistema de Informações Ambulatoriais referentes a “mamografia bilateral para rastreamento” de janeiro/2015 a dezembro/2021. As análises foram feitas por região e para o Brasil. Calculou-se a média de exames em cada mês do ano com base nos dados de 2015 a 2019, a qual foi comparada, mensalmente, com o quantitativo de exames em 2020 e 2021, obtendo-se a diferença bruta e percentual entre esses valores. A mesma análise foi realizada para o número total de exames em 2020 e 2021, individualmente, e para os dois anos em conjunto. Em 2020 houve quedas no número de exames que variaram de 25% (Norte) a 48% (Nordeste), culminando em 1,749 milhão de exames a menos no país (queda de 44%). Em 2021, a região Centro-Oeste apresentou quantitativo de exames 11% superior ao esperado, enquanto as demais regiões apresentaram quedas entre 17% (Norte) e 27% (Sudeste/Sul), culminando em negativo de 927 mil exames no país (redução de 23%). Na análise conjunta (2020/2021), encontraram-se reduções que variaram de 11% (Centro-Oeste) a 35% (Sudeste/Sul), culminando em negativo de 2,676 milhões de procedimentos no Brasil (queda de 33%).