RESUMEN
Infections with Flaviviridae viruses, such as hepatitis C (HCV), dengue (DENV), and yellow fever (YFV) viruses, are major public health problems worldwide. In the case of HCV, treatment is associated with drug resistance and high costs, while there is no clinically approved therapy for DENV and YFV. Consequently, there is still a need for new chemotherapies with alternative modes of action. We have previously identified novel 2-hydroxypyrazino[1,2-a]indole-1,3(2H,4H)-diones as metal-chelating inhibitors targeting HCV RNA replication. Here, by utilizing a structure-based approach, we rationally designed a second series of compounds by introducing various substituents at the indole core structure and at the imidic nitrogen, to improve specificity against the RNA-dependent RNA polymerase (RdRp). The resulting derivatives were evaluated for their potency against HCV genotype 1b, DENV2, and YFV-17D using stable replicon cell lines. The most favorable substitution was nitro at position 6 of the indole ring (compound 36), conferring EC50 1.6 µM against HCV 1b and 2.57 µΜ against HCV 1a, with a high selectivity index. Compound 52, carrying the acetohydroxamic acid functionality (-CH2CONHOH) on the imidic nitrogen, and compound 78, the methyl-substituted molecule at the position 4 indolediketopiperazine counterpart, were the most effective against DENV and YFV, respectively. Interestingly, compound 36 had a high genetic barrier to resistance and only one resistance mutation was detected, T181I in NS5B, suggesting that the compound target HCV RdRp is in accordance with our predicted model.
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Antivirales , Hepacivirus , Indoles , Replicación Viral , Replicación Viral/efectos de los fármacos , Antivirales/farmacología , Antivirales/química , Humanos , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Hepacivirus/fisiología , Indoles/farmacología , Indoles/química , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , ARN Polimerasa Dependiente del ARN/metabolismo , Proteínas no Estructurales Virales/metabolismo , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/genética , Línea Celular , Flaviviridae/efectos de los fármacos , Flaviviridae/genética , Relación Estructura-Actividad , Virus del Dengue/efectos de los fármacos , Virus del Dengue/genética , Virus de la Fiebre Amarilla/efectos de los fármacos , Virus de la Fiebre Amarilla/genéticaRESUMEN
The pollution caused by heavy metals (HMs) represents a global concern due to their serious environmental threat. Photosynthetic cyanobacteria have a natural niche and the ability to remediate HMs such as cadmium. However, their practical application is hindered by a low tolerance to HMs and issues related to recycling. In response to these challenges, this study focuses on the development and evaluation of engineered cyanobacteria-based living materials for HMs bioremediation. Genes encoding phytochelatins (PCSs) and metallothioneins (MTs) were introduced into the model cyanobacterium Synechocystis sp. PCC 6803, creating PM/6803. The strain exhibited improved tolerance to multiple HMs and effectively removed a combination of Cd2+, Zn2+, and Cu2+. Using Cd2+ as a representative, PM/6803 achieved a bioremediation rate of approximately 21 µg of Cd2+/OD750 under the given test conditions. To facilitate its controllable application, PM/6803 was encapsulated using sodium alginate-based hydrogels (PM/6803@SA) to create "living materials" with different shapes. This system was feasible, biocompatible, and effective for removing Cd2+ under simulated conditions of zebrafish and mice models. Briefly, in vitro application of PM/6803@SA efficiently rescued zebrafish from polluted water containing Cd2+, while in vivo use of PM/6803@SA significantly decreased the Cd2+ content in mice bodies and restored their active behavior. The study offers feasible strategies for HMs bioremediation using the interesting biomaterials of engineered cyanobacteria both in vitro and in vivo.
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Biodegradación Ambiental , Metales Pesados , Pez Cebra , Animales , Metales Pesados/metabolismo , Metales Pesados/química , Ratones , Synechocystis/metabolismo , Synechocystis/genética , Metalotioneína/genética , Metalotioneína/metabolismo , Hidrogeles/química , Fitoquelatinas/metabolismo , Cadmio/metabolismo , Cadmio/química , Cianobacterias/metabolismo , Cianobacterias/genética , Alginatos/química , Alginatos/metabolismoRESUMEN
The excessive usage of agrochemicals, including pesticides, along with various reckless human actions, has ensued discriminating prevalence of pesticides and heavy metals (HMs) in crop plants and the environment. The enhanced exposure to these chemicals is a menace to living organisms. The pesticides may get bioaccumulated in the food chain, thereby leading to several deteriorative changes in the ecosystem health and a rise in the cases of some serious human ailments including cancer. Further, both HMs and pesticides cause some major metabolic disturbances in plants, which include oxidative burst, osmotic alterations and reduced levels of photosynthesis, leading to a decline in plant productivity. Moreover, the synergistic interaction between pesticides and HMs has a more serious impact on human and ecosystem health. Various attempts have been made to explore eco-friendly and environmentally sustainable methods of improving plant health under HMs and/or pesticide stress. Among these methods, the employment of PGPR can be a suitable and effective strategy for managing these contaminants and providing a long-term remedy. Although, the application of PGPR alone can alleviate HM-induced phytotoxicities; however, several recent reports advocate using PGPR with other micro- and macro-organisms, biochar, chelating agents, organic acids, plant growth regulators, etc., to further improve their stress ameliorative potential. Further, some PGPR are also capable of assisting in the degradation of pesticides or their sequestration, reducing their harmful effects on plants and the environment. This present review attempts to present the current status of our understanding of PGPR's potential in the remediation of pesticides and HMs-contaminated soil for the researchers working in the area.
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Biodegradación Ambiental , Metales Pesados , Plaguicidas , Contaminantes del Suelo , Metales Pesados/metabolismo , Metales Pesados/análisis , Contaminantes del Suelo/metabolismo , Contaminantes del Suelo/análisis , Plaguicidas/metabolismo , Plaguicidas/análisis , Microbiología del Suelo , Suelo/química , Plantas/metabolismo , Plantas/efectos de los fármacosRESUMEN
The large Bunyavirales order includes several families of viruses with a segmented ambisense (-) RNA genome and a cytoplasmic life cycle that starts by synthesizing viral mRNA. The initiation of transcription, which is common to all members, relies on an endonuclease activity that is responsible for cap-snatching. In La Crosse virus, an orthobunyavirus, it has previously been shown that the cap-snatching endonuclease resides in the N-terminal domain of the L protein. Orthobunyaviruses are transmitted by arthropods and cause diseases in cattle. However, California encephalitis virus, La Crosse virus and Jamestown Canyon virus are North American species that can cause encephalitis in humans. No vaccines or antiviral drugs are available. In this study, three known Influenza virus endonuclease inhibitors (DPBA, L-742,001 and baloxavir) were repurposed on the La Crosse virus endonuclease. Their inhibition was evaluated by fluorescence resonance energy transfer and their mode of binding was then assessed by differential scanning fluorimetry and microscale thermophoresis. Finally, two crystallographic structures were obtained in complex with L-742,001 and baloxavir, providing access to the structural determinants of inhibition and offering key information for the further development of Bunyavirales endonuclease inhibitors.
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Antivirales , Endonucleasas , Virus La Crosse , Triazinas , Virus La Crosse/efectos de los fármacos , Virus La Crosse/enzimología , Antivirales/farmacología , Antivirales/química , Endonucleasas/antagonistas & inhibidores , Endonucleasas/metabolismo , Endonucleasas/química , Dibenzotiepinas , Morfolinas/farmacología , Morfolinas/química , Piridonas/farmacología , Piridonas/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Transferencia Resonante de Energía de Fluorescencia , Humanos , Animales , Proteínas Virales/antagonistas & inhibidores , Proteínas Virales/química , Proteínas Virales/metabolismoRESUMEN
Titanium-45 (45Ti) is a radionuclide with excellent physical characteristics for use in positron emission tomography (PET) imaging, including a moderate half-life (3.08 h), decay by positron emission (85%), and a low mean positron energy of 0.439 MeV. However, challenges associated with titanium chemistry have led to the underdevelopment of this radionuclide for incorporation into radiopharmaceuticals. Expanding on our recent studies, which showed promising results for the complexation of 45Ti with the tris hydroxypyridinone (THPMe) chelator, the current work aimed to optimize the chemistry and imaging attributes of [45Ti]Ti-THP-PSMA as a new PET radiopharmaceutical. Methods. Radiolabeling of THP-PSMA was optimized with [45Ti]Ti-citrate at varying pHs and masses of the precursor. The stability of the radiolabeled complex was assessed in mouse serum for up to 6 h. The affinity of [45Ti]Ti-THP-PSMA for prostate-specific membrane antigen (PSMA) was assessed using LNCaP (PSMA +) and PC3 (PSMA -) cell lines. In vivo imaging and biodistribution analysis were performed in tumor-bearing xenograft mouse models to confirm the specificity of the tumor uptake. Results. > 95% of radiolabeling was achieved with a high specific activity of 5.6 MBq/nmol under mild conditions. In vitro cell binding studies showed significant binding of the radiolabeled complex with the PSMA-expressing LNCaP cell line (11.9 ± 1.5%/mg protein-bound activity) compared to that with the nonexpressing PC3 cells (1.9 ± 0.4%/mg protein-bound activity). In vivo imaging and biodistribution studies confirmed specific uptake in LNCaP tumors (1.6 ± 0.27% ID/g) compared to that in PC3 tumors (0.39 ± 0.2% ID/g). Conclusion. This study showed a simple one-step radiolabeling method for 45Ti with THP-PSMA under mild conditions (pH 8 and 37 °C). In vitro cell studies showed promise, but in vivo tumor xenograft studies indicated low tumor uptake. Overall, this study shows the need for more chelators for 45Ti for the development of a PET radiopharmaceutical for cancer imaging.
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Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias de la Próstata , Masculino , Humanos , Animales , Ratones , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Radiofármacos , Neoplasias de la Próstata/metabolismo , Radioquímica , Distribución Tisular , Titanio , Glutamato Carboxipeptidasa II/metabolismo , Antígenos de Superficie/metabolismo , Tomografía de Emisión de Positrones , Radioisótopos , Quelantes , Línea Celular TumoralRESUMEN
BACKGROUND: Alzheimer's disease (AD) is the most prevalent age-related dementia, and, despite numerous attempts to halt or reverse its devastating progression, no effective therapeutics have yet been confirmed clinically. However, one class of agents that has shown promise is certain metal chelators. OBJECTIVE: For the novel assessment of the effect of oral administration of 1,10-phenanthroline-5-amine (PAA) on the severity of amyloid plaque load, we used a transgenic (Tg) mouse model with inserted human autosomally dominant (familial) AD genes: amyloid-ß protein precursor (AßPP) and tau. METHODS: AßPP/Tau transgenic mice that model AD were allotted into one of two groups. The control group received no treatment while the experimental group received PAA in their drinking water starting at 4 months of age. All animals were sacrificed at 1 year of age and their brains were stained with two different markers of amyloid plaques, Amylo-Glo+ and HQ-O. RESULTS: The control animals exhibited numerous dense core plaques throughout the neo- and allo- cortical brain regions. The experimental group treated with PAA, however, showed 62% of the amyloid plaque burden seen in the control group. CONCLUSIONS: Oral daily dosing with PAA will significantly reduce the amyloid plaque burden in transgenic mice that model AD. The underlying mechanism for this protection is not fully known; however, one proposed mechanism involves inhibiting the "metal-seeding" of Aß.
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Enfermedad de Alzheimer , Ratones , Humanos , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Fenantrolinas/uso terapéutico , Fenantrolinas/metabolismo , Fenantrolinas/farmacología , Placa Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Ratones Transgénicos , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Péptidos beta-Amiloides/metabolismoRESUMEN
Metalloenzymes are central to the regulation of a wide range of essential viral and parasitic functions, including protein degradation, nucleic acid modification, and many others. Given the impact of infectious diseases on human health, inhibiting metalloenzymes offers an attractive approach to disease therapy. Metal-chelating agents have been expansively studied as antivirals and antiparasitics, resulting in important classes of metal-dependent enzyme inhibitors. This review provides the recent advances in targeting the metalloenzymes of viruses and parasites that impose a significant burden on global public health, including influenza A and B, hepatitis B and C, and human immunodeficiency viruses as well as Trypanosoma brucei and Trypanosoma cruzi.
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Essential trace metals like zinc (Zn), iron (Fe), and copper (Cu) play an important physiological role in the metabolomics and healthy functioning of body organs, including the brain. However, abnormal accumulation of trace metals in the brain and dyshomeostasis in the different regions of the brain have emerged as contributing factors in neuronal degeneration, Aß aggregation, and Tau formation. The link between these essential trace metal ions and the risk of AD has been widely studied, although the conclusions have been ambiguous. Despite the absence of evidence for any clinical benefit, therapeutic chelation is still hypothesized to be a therapeutic option for AD. Furthermore, the parameters like bioavailability, ability to cross the BBB, and chelation specificity must be taken into consideration while selecting a suitable chelation therapy. The data in this review summarizes that the primary intervention in AD is brain metal homeostasis along with brain metal scavenging. This review evaluates the impact of different trace metals (Cu, Zn, Fe) on normal brain functioning and their association with neurodegeneration in AD. Also, it investigates the therapeutic potential of metal chelators in the management of AD. An extensive literature search was carried out on the "Web of Science, PubMed, Science Direct, and Google Scholar" to investigate the effect of trace elements in neurological impairment and the role of metal chelators in AD. In addition, the current review highlights the advantages and limitations of chelation therapies and the difficulties involved in developing selective metal chelation therapy in AD patients.
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Enfermedad de Alzheimer , Oligoelementos , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Terapia por Quelación , Péptidos beta-Amiloides , Quelantes/uso terapéutico , Quelantes/farmacología , Cobre , Oligoelementos/uso terapéutico , Zinc/uso terapéuticoRESUMEN
[NiFe]-hydrogenases are used by several human pathogens to catalyze the reversible conversion between molecular hydrogen and protons and electrons. Hydrogenases provide an increased metabolic flexibility for pathogens, such as Escherichia coli and Helicobacter pylori, by allowing the use of molecular hydrogen as an energy source to promote survival in anaerobic environments. With the rise of antimicrobial resistance and the desire for novel therapeutics, the [NiFe]-hydrogenases are alluring targets. Inhibiting the nickel insertion pathway of [NiFe]-hydrogenases is attractive as this pathway is required for the generation of functional enzymes and is orthogonal to human biochemistry. In this work, nickel availability for the production and function of E. coli [NiFe]-hydrogenase was explored through immunoblot and activity assays. Whole-cell hydrogenase activities were assayed in high throughput against a small molecule library of known bioactives. Iodoquinol was identified as a potential inhibitor of the nickel biosynthetic pathway of [NiFe]-hydrogenase through a two-step screening process, but further studies with immunoblot assays showed confounding effects dependent on the cell growth phase. This study highlights the significance of considering the growth phenotype for whole-cell based assays overall and its effects on various cellular processes influenced by metal trafficking and homeostasis.
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Antiinfecciosos , Hidrogenasas , Escherichia coli/metabolismo , Humanos , Hidrógeno/metabolismo , Hidrogenasas/metabolismo , Yodoquinol , Níquel/metabolismo , ProtonesRESUMEN
Ferroptosis is a necrotic cell death caused by lipid oxidation that may be responsible for neural degeneration in Parkinson's disease. We assessed whether three neuronal cell lines are sensitive to killing by ferroptosis. Ferroptosis inducer erastin killed LUHMES neurons at sub-micromolar concentrations, whereas neuronal cells derived from SH-SY5Y cells or neural stem cells were at least 50-fold less sensitive. LUHMES differentiated neurons were likewise sensitive to killing by RSL3 or ML210, inhibitors of the glutathione peroxidase 4 enzyme (GPX4) that consumes GSH to detoxify lipid peroxides. Additional assays showed that erastin, RSL3, and ML210 increased lipid peroxide levels, and that LUHMES neurons were protected from both peroxide accumulation and cell death by ferrostatin-1. A possible role of iron was assessed by evaluating the effects of five metal chelators on cytotoxicity of erastin and RSL3. LUHMES neurons were protected from RSL3 by three of the chelators, 2,3-dimercapto-1-propanesulfonic acid (DMPS), deferoxiprone (DFX), and deferiprone (DFP). Collectively, these results demonstrate the vulnerability of LUHMES neurons to ferroptosis by chemical treatments that disrupt glutathione synthesis, lipid peroxide detoxification, or iron metabolism. The same vulnerabilities may occur in CNS neurons, which reportedly generate low levels of GSH and metallothioneins, limiting their ability to neutralize oxidative stresses and toxic metals. These results suggest a rationale and methods to search for environmental toxicants that may exploit these vulnerabilities and promote neurodegenerative diseases.
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Ferroptosis , Neuroblastoma , Humanos , Carbolinas/toxicidad , Quelantes , Deferiprona , Neuronas Dopaminérgicas/metabolismo , Glutatión/metabolismo , Hierro/metabolismo , Hierro/toxicidad , Peróxidos Lipídicos , Fosfolípido Hidroperóxido Glutatión Peroxidasa , UnitiolRESUMEN
Hydroxypyridinones (HPs) are recognized as excellent chemical tools for engineering a diversity of metal chelating agents, with high affinity for hard metal ions, exhibiting a broad range of activities and applications, namely in medical, biological and environmental contexts. They are easily made and functionalizable towards the tuning of their pharmacokinetic properties or the improving of their metal complex thermodynamic stabilities. In this review, an analysis of the recently published works on hydroxypyridinone-based ligands, that have been mostly addressed for environmental applications, namely for remediation of hard metal ion ecotoxicity in living beings and other biological matrices is carried out. In particular, herein the most recent developments in the design of new chelating systems, from bidentate mono-HP to polydentate multi-HP derivatives, with a structural diversity of soluble or solid-supported backbones are outlined. Along with the ligand design, an analysis of the relationship between their structures and activities is presented and discussed, namely associated with the metal affinity and the thermodynamic stability of the corresponding metal complexes.
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Complejos de Coordinación , Hierro , Quelantes/química , Hierro/química , Ligandos , MetalesRESUMEN
Carbapenemases such as metallo-ß-lactamases (MBLs) are spreading among Gram-negative bacterial pathogens. Infections due to these multidrug-resistant bacteria constitute a major global health challenge. Therapeutic strategies against carbapenemase producing bacteria include ß-lactamase inhibitor combinations. Nitroxoline is a broad-spectrum antibiotic with restricted indication for urinary tract infections. In this study, we report on nitroxoline as an inhibitor of MBLs. We investigate the structure-activity relationships of nitroxoline derivatives considering in vitro MBL inhibitory potency in a fluorescence based assay using purified recombinant MBLs, NDM-1 and VIM-1. We investigated the most potent nitroxoline derivative in combination with imipenem against clinical isolates as well as transformants producing MBL by broth microdilution and time-kill kinetics. Our findings demonstrate that nitroxoline derivatives are potent MBL inhibitors and in combination with imipenem overcome MBL-mediated carbapenem resistance.
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Antibacterianos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Nitroquinolinas/farmacología , Inhibidores de beta-Lactamasas/farmacología , beta-Lactamasas/metabolismo , Antibacterianos/síntesis química , Antibacterianos/química , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Bacterias Gramnegativas/enzimología , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Nitroquinolinas/síntesis química , Nitroquinolinas/química , Proteínas Recombinantes/aislamiento & purificación , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad , Inhibidores de beta-Lactamasas/síntesis química , Inhibidores de beta-Lactamasas/química , beta-Lactamasas/aislamiento & purificaciónRESUMEN
Although melatonin is an astonishing molecule, it is possible that chemistry will help in the discovery of new compounds derived from it that may exceed our expectations regarding antioxidant protection and perhaps even neuroprotection. This review briefly summarizes the significant amount of data gathered to date regarding the multiple health benefits of melatonin and related compounds. This review also highlights some of the most recent directions in the discovery of multifunctional pharmaceuticals intended to act as one-molecule multiple-target drugs with potential use in multifactorial diseases, including neurodegenerative disorders. Herein, we discuss the beneficial activities of melatonin derivatives reported to date, in addition to computational strategies to rationally design new derivatives by functionalization of the melatonin molecular framework. It is hoped that this review will promote more investigations on the subject from both experimental and theoretical perspectives.
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Melatonina/química , Melatonina/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Animales , Antioxidantes/metabolismo , HumanosRESUMEN
A series of naringenin derivatives were designed and synthesized as multifunctional anti-Alzheimer's disease (AD) agents. The results showed that these derivatives displayed moderate-to-good acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities at the micromolar range (IC50, 12.91 ~ 62.52 µM for AChE and 0.094 ~ 13.72 µM for BuChE). Specifically, compound 1 showed the highest inhibitory activity against BuChE with the IC50 value of (0.094 ± 0.0054) µM. A Lineweaver-Burk plot and molecular docking studies demonstrated that 1 targeted both the catalytically active site (CAS) and the peripheral anion site (PAS) of BuChE. Besides, all derivatives showed excellent hydroxyl free radicals (·OH) scavenging ability than vitamin C and cyclic voltammetry results displayed that 1 could effectively scavenge superoxide anion radical (·O2-). In addition, compound 1 displayed good metal chelating properties and had anti-Aß aggregation activities. Therefore, compound 1 might be the potential anti-AD agent for further developments.
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Carbamatos/farmacología , Quelantes/farmacología , Inhibidores de la Colinesterasa/farmacología , Flavanonas/farmacología , Depuradores de Radicales Libres/farmacología , Acetilcolinesterasa/química , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Animales , Butirilcolinesterasa/química , Butirilcolinesterasa/metabolismo , Carbamatos/síntesis química , Carbamatos/metabolismo , Quelantes/síntesis química , Quelantes/metabolismo , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/metabolismo , Diseño de Fármacos , Electrophorus , Flavanonas/síntesis química , Flavanonas/metabolismo , Depuradores de Radicales Libres/síntesis química , Depuradores de Radicales Libres/metabolismo , Caballos , Cinética , Simulación del Acoplamiento Molecular , Estructura Molecular , Fragmentos de Péptidos/metabolismo , Unión Proteica , Multimerización de Proteína/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
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-ß (Aß) have been proposed as one of the major causes of the disease, the mechanism of clearing Aß 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 Aß 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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Enfermedad de Alzheimer/metabolismo , Amiloide/metabolismo , Encéfalo/metabolismo , Proteína ADAM10/metabolismo , Enfermedad de Alzheimer/etiología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Barrera Hematoencefálica/metabolismo , Quelantes/metabolismo , Cobre/metabolismo , Humanos , Insulisina/metabolismo , Hierro/metabolismo , Proteínas de la Membrana/metabolismo , Metales/metabolismo , Neprilisina/metabolismo , Oxidación-Reducción , ProteolisisRESUMEN
BACKGROUND: Alzheimer's disease (AD) is the most prevalent cause of cognitive impairment and dementia worldwide. The pathobiology of the disease has been studied in the form of several hypotheses, ranging from oxidative stress, amyloid-beta (Aß) aggregation, accumulation of tau forming neurofibrillary tangles (NFT) through metal dysregulation and homeostasis, dysfunction of the cholinergic system, and to inflammatory and autophagic mechanism. However, none of these hypotheses has led to confirmed diagnostics or approved cure for the disease. OBJECTIVE: This review is aimed as a basic and an encyclopedic short course into metals in AD and discusses the advances in chelation strategies and developments adopted in the treatment of the disease. Since there is accumulating evidence of the role of both biometal dyshomeostasis (iron (Fe), copper (Cu), and zinc (Zn)) and metal-amyloid interactions that lead to the pathogenesis of AD, this review focuses on unraveling therapeutic chelation strategies that have been considered in the treatment of the disease, aiming to sequester free and protein-bound metal ions and reducing cerebral metal burden. Promising compounds possessing chemically modified moieties evolving as multi-target ligands used as anti-AD drug candidates are also covered. RESULTS AND CONCLUSION: Several multidirectional and multifaceted studies on metal chelation therapeutics show the need for improved synthesis, screening, and analysis of compounds to be able to effectively present chelating anti-AD drugs. Most drug candidates studied have limitations in their physicochemical properties; some enhance redistribution of metal ions, while others indirectly activate signaling pathways in AD. The metal chelation process in vivo still needs to be established and the design of potential anti-AD compounds that bi-functionally sequester metal ions as well as inhibit the Aß aggregation by competing with the metal ions and reducing metal-induced oxidative damage and neurotoxicity may signal a bright end in chelation-based therapeutics of AD.
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Enfermedad de Alzheimer , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides , Quelantes/uso terapéutico , Cobre , Humanos , Iones , Hierro , Metales , Preparaciones Farmacéuticas , ZincRESUMEN
Zinc is a redox-inert trace element that is second only to iron in abundance in biological systems. In cells, zinc is typically buffered and bound to metalloproteins, but it may also exist in a labile or chelatable (free ion) form. Zinc plays a critical role in prokaryotes and eukaryotes, ranging from structural to catalytic to replication to demise. This review discusses the influential properties of zinc on various mechanisms of bacterial proliferation and synergistic action as an antimicrobial element. We also touch upon the significance of zinc among eukaryotic cells and how it may modulate their survival and death through its inhibitory or modulatory effect on certain receptors, enzymes, and signaling proteins. A brief discussion on zinc chelators is also presented, and chelating agents may be used with or against zinc to affect therapeutics against human diseases. Overall, the multidimensional effects of zinc in cells attest to the growing number of scientific research that reveal the consequential prominence of this remarkable transition metal in human health and disease.
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Alzheimer´s disease (AD) is the most common and severe age-dependent neurodegenerative disorder worldwide. Notwithstanding the large amount of research dedicated to both the elucidation of this pathology and the development of an effective drug, the multifaceted nature and complexity of the disease are certainly a rationale for the absence of cure so far. Currently available drugs are used, mainly to compensate the decline of the neurotransmitter acetylcholine by acetylcholinesterase (AChE) inhibition, though they only provide temporary symptomatic benefits and cannot stop AD progression. Although the multiple factors that contribute to trigger AD onset and progression are not yet fully understood, several pathological features and underneath pathways have been recognized to contribute to its pathology, such as metal dyshomeostasis, protein misfolding, oxidative stress and neurotransmitter deficiencies, some of them being interconnected. Thus, there is widespread recent interest in the development of multitarget-directed ligands (MTDLs) for simultaneous interaction with several pathological targets of AD. In this review, a selection of the most recent reports (2016-up to present) on metal chelators of MTDLs with multifunctionalities is presented. These compounds enable the hitting of several AD targets or pathways, such as modulation of specific biometal ions (e.g., Cu, Fe, Zn) and of protein misfolding (ß-amyloid and tau protein), anti-oxidant activity and AChE inhibition. The properties found for these hybrids are discussed in comparison with the original reference compounds, some MTDLs being outlined as leading compounds for pursuing future studies in view of efficient potential applications in AD therapy.
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Enfermedad de Alzheimer , Acetilcolinesterasa , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides , Antioxidantes , Quelantes/farmacología , Quelantes/uso terapéutico , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/uso terapéutico , HumanosRESUMEN
Melanoma is an aggressive and highly metastatic type of skin cancer where the design of new therapies is of utmost importance for the clinical management of the disease. Thus, we have aimed to investigate the mode of action by which a novel methylated analogue of L-Mimosine (e.g., L-SK-4) exerts its therapeutic potency in an in vitro model of malignant melanoma. Cytotoxicity was assessed by the Alamar Blue assay, oxidative stress by commercially available kits, ROS generation, caspase 3/7 activation and mitochondrial membrane depolarisation by flow cytometry, expression of apoptosis-related proteins by western immunoblotting and profiling of lipid biosynthesis by a metabolomic approach. Overall, higher levels of ROS, sphingolipids and apoptosis were induced by L-SK-4 suggesting that the compound's therapeutic potency is mediated through elevated ROS levels which promote the upregulation of sphingolipid (ceramide) biosynthesis thus leading to the activation of both extrinsic and intrinsic apoptosis, in an experimental model of malignant melanoma.
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Antineoplásicos/farmacología , Melanoma/tratamiento farmacológico , Mimosina/farmacología , Neoplasias Cutáneas/tratamiento farmacológico , Animales , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Ceramidas/metabolismo , Ceramidas/farmacología , Citometría de Flujo , Humanos , Melanoma/patología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Metilación , Ratones , Mimosina/análogos & derivados , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Cutáneas/patologíaRESUMEN
Terpyridine derivatives are known from their broad application including anticancer properties. In this work we present the newly synthesized 4'-phenyl-2,2':6',2â³-terpyridine group with high antiproliferative activity. We suggest that these compounds influence cellular redox homeostasis. Cancer cells are particularly susceptible to any changes in the redox balance because of their handicapped and inefficient antioxidant cellular systems. The antiproliferative activity of the studied compounds was tested on five different cell lines that represent several types of tumours; glioblastoma, leukemia, breast, pancreatic and colon. Additionally, we also tested their selectivity towards normal cells. We performed molecular biology studies in order to detect the response of a cell to its treatment with the compounds that were tested. We looked at the in-depth changes in the proteins and cellular pathways that lead to cell cycle inhibition (G0/G1 and S), and consequently, death on the apoptosis and autophagy pathways. We proved that the studied compounds targeted DNA as well. Special attention was paid to the targets connected with ROS generation.