RESUMO
Alzheimer's disease (AD) is an incurable neurodegenerative disease that leads to the progressive and irreversible loss of mental functions. The amyloid beta (Aß) peptide involved in the disease is responsible for the production of damaging reactive oxygen species (ROS) when bound to Cu ions. A therapeutic approach that consists of removing Cu ions from Aß to alter this deleterious interaction is currently being developed. In this context, we report the ability of five different 12-membered thiaazacyclen ligands to capture Cu from Aß and to redox silence it. We propose that the presence of a sole sulfur atom in the ligand increases the rate of Cu capture and removal from Aß, while the kinetic aspect of the chelation was an issue encountered with the 4N parent ligand. The best ligand for removing Cu from Aß and inhibiting the associated ROS production is the 1-thia-4,7,10-triazacyclododecane [3N1S]. Indeed the replacement of more N by S atoms makes the corresponding Cu complexes easier to reduce and thus able to produce ROS on their own. In addition, the ligand with three sulfur atoms has a weaker affinity for CuII than Aß, and is thus unable to remove Cu from CuAß.
Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Humanos , Peptídeos beta-Amiloides/química , Espécies Reativas de Oxigênio/metabolismo , Ligantes , Doença de Alzheimer/metabolismo , Cobre/químicaRESUMO
Alzheimer's disease (AD) is one of the most common of the multifactorial diseases and is characterized by a range of abnormal molecular processes, such as the accumulation of extracellular plaques containing the amyloid-ß (Aß) peptides and dyshomeostasis of copper in the brain. In this study, we have investigated the effect of CuII on the aggregation of Aß1-40 and Aß4-40 , representing the two most prevalent families of Aß peptides, that is, the full length and N-truncated peptides. Both families are similarly abundant in healthy and AD brains. For either of the studied peptides, substoichiometric CuII concentrations accelerated aggregation, whereas superstoichiometric CuII inhibited fibril formation, likely by stabilizing the oligomers. The addition of either Aß4-40 or substoichiometric CuII affected the aggregation profile of Aß1-40 , by yielding shorter and thicker fibrils; amorphous aggregates were formed in the presence of a molar excess of CuII . The similarity of these two effects can be attributed to the increase in the positive charge on the Aß N terminus, caused both by CuII complexation and N truncation at position 4. Our findings provide a better understanding of the biological Aß aggregation process as these two Aß species and CuII coexist and interact under physiological conditions.
RESUMO
Converging evidence indicates that neurotoxicity and memory impairment in Alzheimer's disease is induced by brain accumulation of soluble amyloid-ß oligomers (AßOs). Physiological metals are poorly distributed and concentrated in the senile plaques typical of Alzheimer's disease, where they may be coordinated to the amyloid-ß peptide (Aß). Indeed, zinc and copper increase Aß oligomerization and toxicity. Metal-protein attenuating compounds represent a class of agents proposed for Alzheimer's disease treatment, as they reduce abnormal interactions of metal ions with Aß, inhibit Aß oligomerization and prevent deleterious redox reactions in the brain. The present work investigates the protective action of an isoniazid-derived aroylhydrazone, INHHQ, on AßO-induced memory impairment. Systemic administration of a single dose of INHHQ (1 mg/kg) prevented both short-term and long-term memory impairment caused by AßOs in mice. In-vitro studies showed that INHHQ prevents Cu(Aß)-catalyzed production of reactive oxygen species. Although the mechanism of protection by INHHQ is not yet fully understood at a molecular level, the results reported herein certainly point to the value of aroylhydrazones as promising neuroprotective agents in Alzheimer's disease and related disorders.
Assuntos
Hidrazonas/farmacologia , Isoniazida/farmacologia , Transtornos da Memória/tratamento farmacológico , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/efeitos dos fármacos , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Isoniazida/análogos & derivados , Masculino , Camundongos , Fármacos Neuroprotetores/uso terapêutico , Oxirredução/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Moulds inhabiting mineral-based materials may cause their biodeterioration, contributing to inestimable losses, especially in the case of cultural heritage objects and architectures. Fungi in mouldy buildings may also pose a threat to human health and constitute the main etiological factor in building related illnesses. In this context, research into novel compounds with antifungal activity is of high importance. The aim of this study was to evaluate the antifungal activity of polyoxometalate-ionic liquids (POM-ILs) and their use in the eradication of moulds from historical brick. In the disc diffusion assay, all the tested POM-ILs inhibited growth of a mixed culture of moulds including Engyodontium album, Cladosporium cladosporioides, Alternaria alternata and Aspergillus fumigatus. These were isolated from the surfaces of historical brick barracks at the Auschwitz II-Birkenau State Museum in Oswiecim, Poland. POM-IL coatings on historical brick samples, under model conditions, showed that two compounds demonstrated very high antifungal activity, completely limiting mould growth and development. The antifungal activity of the POM-ILs appeared to stem from their toxic effects on conidia, as evidenced by environmental scanning transmission electron microscopy observations. The results herein indicated that POM-ILs are promising disinfectant materials for use not only on historical objects, but probably also on other mineral-based materials.
Assuntos
Antifúngicos/farmacologia , Materiais de Construção/microbiologia , Desinfetantes/farmacologia , Fungos/crescimento & desenvolvimento , Líquidos Iônicos , Compostos de Tungstênio/farmacologia , Fungos/efeitos dos fármacosRESUMO
Several diseases share misfolding of different peptides and proteins as a key feature for their development. This is the case of important neurodegenerative diseases such as Alzheimer's and Parkinson's diseases and type II diabetes mellitus. Even more, metal ions such as copper and zinc might play an important role upon interaction with amyloidogenic peptides and proteins, which could impact their aggregation and toxicity abilities. In this review, the different coordination modes proposed for copper and zinc with amyloid-ß, α-synuclein and IAPP will be reviewed as well as their impact on the aggregation, and ROS production in the case of copper. In addition, a special focus will be given to the mutations that affect metal binding and lead to familial cases of the diseases. Different modifications of the peptides that have been observed in vivo and could be relevant for the coordination of metal ions are also described.
RESUMO
Along with aggregation of the amyloid-ß (Aß) peptide and subsequent deposit of amyloid plaques, oxidative stress is an important feature in Alzheimer's disease. Cu bound to Aß is able to produce reactive oxygen species (ROS) by the successive reductions of molecular dioxygen, and the ROS produced contribute to oxidative stress. In vitro, ascorbate consumption parallels ROS production, where ascorbate is the reductant that fuels the reactions. Because the affinity of Cu for Aß is moderate compared to other biomolecules, the rate of ascorbate consumption is a combination of two contributions. The first one is due to peptide-unbound Cu and the second one to peptide-bound Cu complexes. In the present Article, we aim to determine the amounts of the second contribution in the global ascorbate consumption process. It is defined as the intrinsic rate of ascorbate oxidation, which mathematically corresponds to the rate at an infinite peptide to Cu ratio, i.e., without any contribution from peptide-unbound Cu. We show that, for the wild-type Cu(Aß) complex, this value equals 10% of the value obtained for peptide-unbound Cu and that this value is strongly dependent on peptide alterations. By examination of the dependence of the intrinsic rate of ascorbate oxidation, followed by UV-vis spectroscopy, for several altered peptides, we determine some of the key residues that influence ROS production.
Assuntos
Peptídeos beta-Amiloides/química , Cobre/química , Compostos Organometálicos/química , Espécies Reativas de Oxigênio/metabolismo , Sequência de Aminoácidos , OxirreduçãoRESUMO
Cu and Zn ions are essential in most living beings. Their metabolism is critical for health and mis-metabolism can be lethal. In the last two decades, a large body of evidence has reported the role of copper, zinc and iron, and oxidative stress in several neurodegenerative diseases like Alzheimer's, Parkinson's, prion diseases, etc. To what extent this mis-metabolism is causative or a consequence of these diseases is still a matter of research. In this context metallothioneins (MTs) appear to play a central gate-keeper role in controlling aberrant metal-protein interactions. MTs are small proteins that can bind high amounts of Zn(ii) and Cu(i) ions in metal-cluster arrangements via their cysteine thiolates. Moreover, MTs are well known antioxidants. The present tutorial outlines the chemistry underlying the interconnection between copper(i/ii) and zinc(ii) coordination to amyloidogenic proteins and MTs, and their redox properties in generation and/or silencing reactive oxygen species (overproduced in oxidative stress) and other reactants. These studies have revealed the coordination chemistry involved in neurodegenerative diseases and the interactions between MTs and amyloidogenic protein metal-complexes (like amyloid-ß, α-synuclein and prion-protein). Overall, the protective role of MTs in neurodegenerative processes is emerging, serving as a foundation for exploring MT chemistry as inspiration for therapeutic approaches.
Assuntos
Proteínas Amiloidogênicas/química , Metalotioneína/química , Animais , HumanosRESUMO
New gold(I) thiolate complexes have been synthesized and characterized, and their physicochemical properties and anticancer activity have been tested. The coordination of PTA derivatives provides optimal hydrophilicity/lipophilicity properties to the complexes, which present high solution stability. Moreover, the complexes show a high anticancer activity against Caco-2 cells, comparable to that of auranofin, and a very low cytotoxic activity against enterocyte-like differentiated cells. Their activity has been shown to produce cell death by apoptosis and arrest of the cell cycle because of interaction with the reductase enzymes and consequent reactive oxygen species production. Some of these new complexes are also able to decrease the necessary dose of 5-fluorouracil, a drug used for the treatment of colon cancer, by a synergistic mechanism.
Assuntos
Antineoplásicos/farmacologia , Neoplasias do Colo/tratamento farmacológico , Fluoruracila/farmacologia , Compostos Organoáuricos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Auranofina/farmacologia , Células CACO-2 , Bovinos , Ciclo Celular/efeitos dos fármacos , Ácido Ditionitrobenzoico/química , Estabilidade de Medicamentos , Sinergismo Farmacológico , Humanos , Compostos Organoáuricos/síntese química , Compostos Organoáuricos/química , Espécies Reativas de Oxigênio/metabolismo , Soroalbumina Bovina/metabolismo , Tiorredoxina Redutase 1/antagonistas & inibidoresRESUMO
This study investigates the activity of novel gold(I) and copper(I)/zinc(II) heteronuclear complexes against colon cancer. The synthesised heteronuclear Au(I)-Cu(I) and Au(I)-Zn(II) complexes were characterised and evaluated for their anticancer activity using human colon cancer cell lines (Caco-2). The complexes exhibited potent cytotoxicity, with IC50 values in the low micromolar range, and effectively induced apoptosis in cancer cells. In the case of complex [Cu{Au(Spy)(PTA)}2]PF6 (2), its cytotoxicity is ×10 higher than its mononuclear precursor, while showing low cytotoxicity towards differentiated healthy cells. Mechanistic studies revealed that complex 2 inhibits the activity of thioredoxin reductase, a key enzyme involved in redox regulation, leading to an increase in reactive oxygen species (ROS) levels and oxidative stress, in addition to an alteration in DNA's tertiary structure. Furthermore, the complexes demonstrated a strong binding affinity to bovine serum albumin (BSA), suggesting the potential for effective drug delivery and bioavailability. Collectively, these findings highlight the potential of the investigated heteronuclear Au(I)-Cu(I) and Au(I)-Zn(II) complexes as promising anticancer agents, particularly against colon cancer, through their ability to disrupt redox homeostasis and induce oxidative stress-mediated cell death.
RESUMO
Iron gall ink (IGI), renowned for its indelibility, was the most important writing ink in the Western world from the 15th to the late 19th century. However, it is now known that IGIs induce acid-catalyzed hydrolysis and iron-catalyzed oxidation of the cellulose in historical paper documents. These mechanisms of deterioration cause significant damage to the writing support materials, including color alteration and burn-through appearance, and in the worst scenarios, physical disintegration of the supports. Minimally invasive, long-term effective conservation treatments that tackle the underlying mechanisms of IGI degradation and their corrosion effects are yet to be developed. This study introduces the deployment of hydrophobic and anticorrosive polyoxometalate-ionic liquids (POM-ILs) as colorless coatings to counteract IGI-corrosion of cellulosic supports. Model IGI-containing papers (mockups) were prepared, coated with POM-ILs, and artificially aged to assess the compatibility of POM-ILs with IGI-containing documents. Comprehensive monitoring using colorimetric and scanning electron microscopy-energy-dispersive X-ray spectroscopy (SEM/EDS) analyses showed minimal interference with the aesthetic properties and morphology of the IGI mockups. In addition, polyoxometalates (POMs) with vacant metal atom sites in the cluster shell can be used to coordinate free transition metal ions. The ability of a monolacunary Keggin-type polyoxotungstate to coordinate free Fe(II) from IGI solution was demonstrated using UV-vis analysis. This led to the formation of a dimeric species, [(SiW11O39Fe)2O]K12·28H2O, which was characterized by single-crystal X-ray diffraction. Altogether, this study points to POM-ILs as promising protective coatings for effectively preserving historical IGI-written heritage.
RESUMO
New gold(I) complexes with coordination to 5-fluorouracil (5-FU), an anticancer drug with antibacterial properties, have been synthesised and characterised, and are the first reported examples of 5-FU-Au compounds. These new complexes show high solution stability, even in the presence of a cysteine derivative, and so were evaluated as antibacterial compounds against model Gram-positive and Gram-negative bacteria. All the complexes show excellent antibacterial activity against Gram-positive B. subtilis, most of them improving the activity of 5-FU alone. Furthermore, these new complexes are also active against Gram-negative E. coli, where [Au(5-FU)(PTA)], the complex with the smallest phosphane, is the most bactericidal, 32 times more active than 5-FU on its own.
Assuntos
Antibacterianos , Complexos de Coordenação , Antibacterianos/farmacologia , Ouro/farmacologia , Fluoruracila/farmacologia , Escherichia coli , Bactérias Gram-Negativas , Bactérias Gram-Positivas , Testes de Sensibilidade Microbiana , Complexos de Coordenação/farmacologiaRESUMO
Organo-functionalisation of polyoxometalates (POMs) represents an effective approach to obtain diverse arrays of functional structures and materials, where the introduction of organic moieties into the POM molecules can dramatically change their surface chemistry, charge, polarity, and redox properties. The synergistic combination of POMs and peptides, which perform a myriad of essential roles within cellular biochemistry, including protection and transport in living organisms, leads to functional hybrid materials with unique properties. In this Perspective article, we present the principal synthetic routes to prepare and characterise POM-peptide hybrids, together with a comprehensive description of how their properties - such as redox chemistry, stereochemistry and supramolecular self-assembly - give rise to materials with relevant catalytic, adhesive, and biomedical applications. By presenting the state-of-the-art of the POM-peptide field, we show specifically how emerging chemical approaches can be harnessed to develop tailored POM-peptide materials with synergistic properties for applications in a variety of disciplines.
RESUMO
Developing artificial metalloenzymes that possess a superior performance to their natural counterparts is an attractive concept. Polyoxometalates (POMs) are a class of anionic molecular metal-oxides with excellent redox properties and bioactivity. We have recently introduced "POMlymers" - covalently conjugated POM-peptide hybrid materials - where the polypeptide chain is obtained through a ring-opening polymerisation (ROP) of α-amino acid N-carboxyanhydrides (NCA) on an inorganic POM scaffold. Attracted by the idea of preparing artificial metalloenzymes, here we report the supramolecular self-assembly of POMlymer hybrids into nanoparticles where an optimal environment for catalysis is created. Our results demonstrate that the self-assembly of covalent POMlymers, enhances the peroxidase-like activity of the parent POM anion whereas, in contrast, the catalytic activity for nanoparticles obtained by ionic self-assembly of the same peptide and POM components practically disappears. Furthermore, POMlymer nanoparticles also present antimicrobial and antibiofilm activity against the skin bacterium Staphylococcus epidermidis; whereas, ionic POM-peptide hybrids significantly increase biofilm production and endogenous production of reactive oxygen species. In summary, we present the self-assembly of POMlymer hybrids into nanoparticles and a combination of peroxidase activity and microbiology assays that show that the POM-peptide covalent bond is essential for the stability of the self-assembled nanoparticles and therefore for their catalytic and biological activity.
Assuntos
Metaloproteínas , Compostos de Tungstênio , Ânions , Biofilmes , Peptídeos/farmacologia , Peroxidase , Polieletrólitos , Compostos de Tungstênio/químicaRESUMO
In this paper we describe the synthesis of new N-heterocyclic carbene (NHC) gold(I) derivatives with flavone-derived ligands with a propargyl ether group. The compounds were screened for their antimicrobial and anticancer activities, showing greater activity against bacteria than against colon cancer cells (Caco-2). Complexes [Au(L2b)(IMe)] (1b) and [Au(L2b)(IPr)] (2b) were found to be active against both Gram-positive and Gram-negative strains. The mechanism of action of 1b was evaluated by measurement of thioredoxin reductase (TrxR) and dihydrofolate reductase (DHFR) activity, besides scanning electron microscopy (SEM). Inhibition of the enzyme thioredoxin reductase is not observed in either Escherichia Coli or Caco-2 cells; however, DHFR activity is compromised after incubation of E. coli cells with complex 1b. Moreover, loss of structural integrity and change in bacterial shape is observed in the images obtained from scanning electron microscopy (SEM) after treatment E. coli cells with complex 1b.
RESUMO
Two Keggin polyoxometalates were used as new copper ligands to counteract the effects of CuII(Amyloid-ß) interaction. Their ability to remove CuII from CuII(Amyloid-ß), to stop CuII(Amyloid-ß) induced formation of reactive oxygen species and to restore apo-like self-assembly of CuII(Amyloid-ß) was shown.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Ânions/farmacologia , Quelantes/farmacologia , Cobre/farmacologia , Polieletrólitos/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Ânions/química , Quelantes/síntese química , Quelantes/química , Cobre/química , Humanos , Polieletrólitos/química , Espécies Reativas de Oxigênio/metabolismoRESUMO
The increasing resistance of pathogenic microorganisms against common treatments requires innovative concepts to prevent infection and avoid long-term microbe viability on commonly used surfaces. Here, we report the preparation of a hybrid antimicrobial material based on the combination of microbiocidal polyoxometalate-ionic liquids (POM-ILs) and a biocompatible polymeric support, which enables the development of surface coatings that prevent microbial adhesion. The composite material is based on an antibacterial and antifungal room-temperature POM-IL composed of guanidinium cations (N,N,N',N'-tetramethyl-Nâ³, Nâ³-dioctylguanidinum) combined with lacunary Keggin-type polyoxotungstate anions, [α-SiW11O39]8-. Integration of the antimicrobial POM-IL into the biocompatible, flexible, and stable polymer poly(methyl methacrylate) (PMMA) results in processable films, which are suitable as surface coatings or packaging materials to limit the proliferation and spread of pathogenic microorganisms (e.g., on public transport and hospital surfaces, or in ready-to-eat-food packaging).
RESUMO
The antibacterial activity of imidazole and imidazolium salts is highly dependent upon their lipophilicity, which can be tuned through the introduction of different hydrophobic substituents on the nitrogen atoms of the imidazole or imidazolium ring of the molecule. Taking this into consideration, we have synthesized and characterized a series of imidazole and imidazolium salts derived from L-valine and L-phenylalanine containing different hydrophobic groups and tested their antibacterial activity against two model bacterial strains, Gram-negative E. coli and Gram-positive B. subtilis. Importantly, the results demonstrate that the minimum bactericidal concentration (MBC) of these derivatives can be tuned to fall close to the cytotoxicity values in eukaryotic cell lines. The MBC value of one of these compounds toward B. subtilis was found to be lower than the IC50 cytotoxicity value for the control cell line, HEK-293. Furthermore, the aggregation behavior of these compounds has been studied in pure water, in cell culture media, and in mixtures thereof, in order to determine if the compounds formed self-assembled aggregates at their bioactive concentrations with the aim of determining whether the monomeric species were in fact responsible for the observed antibacterial activity. Overall, these results indicate that imidazole and imidazolium compounds derived from L-valine and L-phenylalanine-with different alkyl lengths in the amide substitution-can serve as potent antibacterial agents with low cytotoxicity to human cell lines.
RESUMO
Metal-targeting drugs are being widely explored as a possible treatment for Alzheimer's disease, but most of these ligands are developed to coordinate Cu(ii). In a previous communication (E. Atrián-Blasco, E. Cerrada, A. Conte-Daban, D. Testemale, P. Faller, M. Laguna and C. Hureau, Metallomics, 2015, 7, 1229-1232) we showed another strategy where Cu(i) was targeted with the PTA (1,3,5-triaza-7-phosphaadamantane) ligand that is able to target Cu(ii) as well, reduce it and keep it in a safe complexed species. Removal of Cu(ii) from the amyloid-ß peptide prevents the stabilization of oligomers and protofibrils and the complexation of Cu(i) also stops the formation of reactive oxygen species. Besides, zinc, which is found in the synaptic cleft at a higher concentration than copper, can hamper the ability of metal-targeting drug candidates, an issue that is still poorly considered and studied. Here we show that PTA fully retains the above described properties even in the presence of zinc, thus fulfilling an additional pre-requisite for its use as a model of Cu(i)-targeting drug candidates in the Alzheimer's disease context.
Assuntos
Adamantano/análogos & derivados , Peptídeos beta-Amiloides/metabolismo , Cobre/metabolismo , Compostos Organofosforados/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Zinco/metabolismo , Adamantano/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/química , Humanos , Ligantes , Multimerização Proteica/efeitos dos fármacosRESUMO
While metal ions such as copper and zinc are essential in biology, they are also linked to several amyloid-related diseases, including Alzheimer's disease (AD). Zinc and copper can indeed modify the aggregation pathways of the amyloid-ß (Aß) peptide, the key component encountered in AD. In addition, the redox active copper ions do produce Reactive Oxygen Species (ROS) when bound to the Aß peptide. While Cu(i) or Cu(ii) or Zn(ii) coordination to the Aß has been extensively studied in the last ten years, characterization of hetero-bimetallic Aß complexes is still scarce. This is also true for the metal induced Aß aggregation and ROS production, for which studies on the mutual influence of the copper and zinc ions are currently appearing. Last but not least, zinc can strongly interfere in therapeutic approaches relying on copper detoxification. This will be exemplified with a biological lead, namely metallothioneins, and with synthetic ligands.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Cobre/metabolismo , Zinco/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/química , Complexos de Coordenação/química , Complexos de Coordenação/metabolismo , Cobre/química , Humanos , Ligantes , Agregados Proteicos , Ligação Proteica , Espécies Reativas de Oxigênio/química , Espécies Reativas de Oxigênio/metabolismo , Zinco/químicaRESUMO
Oxidative stress is linked to the etiology of Alzheimer's disease (AD), the most common cause of dementia in the elderly. Redox active metal ions such as copper catalyze the production of Reactive Oxygen Species (ROS) when bound to the amyloid-ß (Aß) peptide encountered in AD. We propose that this reaction proceeds through a low-populated Cu-Aß state, denoted the "catalytic in-between state" (CIBS), which is in equilibrium with the resting state (RS) of both Cu(i)-Aß and Cu(ii)-Aß. The nature of this CIBS is investigated in the present work. We report the use of complementary spectroscopic methods (X-ray absorption spectroscopy, EPR and NMR) to characterize the binding of Cu to a wide series of modified peptides in the RS. ROS production by the resulting Cu-peptide complexes was evaluated using fluorescence and UV-vis based methods and led to the identification of the amino acid residues involved in the Cu-Aß CIBS species. In addition, a possible mechanism by which the ROS are produced is also proposed. These two main results are expected to affect the current vision of the ROS production mechanism by Cu-Aß but also in other diseases involving amyloidogenic peptides with weakly structured copper binding sites.