RESUMEN
Genetic and epigenetic changes alter gene expression, contributing to cancer. Epigenetic changes in cancer arise from alterations in DNA and histone modifications that lead to tumour suppressor gene silencing and the activation of oncogenes. The acetylation status of histones and non-histone proteins are determined by the histone deacetylases and histone acetyltransferases that control gene transcription. Organoselenium compounds have become promising contenders in cancer therapeutics. Apart from their anti-oxidative effects, several natural and synthetic organoselenium compounds and metabolites act as histone deacetylase inhibitors, which influence the acetylation status of histones and non-histone proteins, altering gene transcription. This review aims to summarise the effect of natural and synthetic organoselenium compounds on histone and non-histone protein acetylation/deacetylation in cancer therapy.
Asunto(s)
Inhibidores de Histona Desacetilasas/farmacología , Neoplasias/tratamiento farmacológico , Compuestos de Organoselenio/farmacología , Acetilación/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Epigénesis Genética/efectos de los fármacos , Código de Histonas/efectos de los fármacos , Código de Histonas/genética , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/metabolismo , Histona Desacetilasas/metabolismo , Histonas/metabolismo , Humanos , Terapia Molecular Dirigida , Nanopartículas , Neoplasias/genética , Neoplasias/metabolismo , Compuestos de Organoselenio/síntesis química , Compuestos de Organoselenio/metabolismo , Procesamiento Proteico-Postraduccional/efectos de los fármacosRESUMEN
Functions of selenium are diverse as antioxidant, anti-inflammation, increased immunity, reduced cancer incidence, blocking tumor invasion and metastasis, and further clinical application as treatment with radiation and chemotherapy. These functions of selenium are mostly related to oxidation and reduction mechanisms of selenium metabolites. Hydrogen selenide from selenite, and methylselenol (MSeH) from Se-methylselenocyteine (MSeC) and methylseleninicacid (MSeA) are the most reactive metabolites produced reactive oxygen species (ROS); furthermore, these metabolites may involve in oxidizing sulfhydryl groups, including glutathione. Selenite also reacted with glutathione and produces hydrogen selenide via selenodiglutathione (SeDG), which induces cytotoxicity as cell apoptosis, ROS production, DNA damage, and adenosine-methionine methylation in the cellular nucleus. However, a more pronounced effect was shown in the subsequent treatment of sodium selenite with chemotherapy and radiation therapy. High doses of sodium selenite were effective to increase radiation therapy and chemotherapy, and further to reduce radiation side effects and drug resistance. In our study, advanced cancer patients can tolerate until 5000 µg of sodium selenite in combination with radiation and chemotherapy since the half-life of sodium selenite may be relatively short, and, further, selenium may accumulates more in cancer cells than that of normal cells, which may be toxic to the cancer cells. Further clinical studies of high amount sodium selenite are required to treat advanced cancer patients.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Selenito de Sodio/uso terapéutico , Glutatión/análogos & derivados , Glutatión/metabolismo , Humanos , Metanol/análogos & derivados , Metanol/metabolismo , Neoplasias/metabolismo , Neoplasias/patología , Compuestos de Organoselenio/metabolismo , Compuestos de Selenio/metabolismo , Selenito de Sodio/metabolismoRESUMEN
The main protease (Mpro or 3CLpro) of SARS-CoV-2 virus is a cysteine enzyme critical for viral replication and transcription, thus indicating a potential target for antiviral therapy. A recent repurposing effort has identified ebselen, a multifunctional drug candidate as an inhibitor of Mpro. Our docking of ebselen to the binding pocket of Mpro crystal structure suggests a noncovalent interaction for improvement of potency, antiviral activity and selectivity. To test this hypothesis, we designed and synthesized ebselen derivatives aimed at enhancing their non-covalent bonds within Mpro. The inhibition of Mpro by ebselen derivatives (0.3 µM) was screened in both HPLC and FRET assays. Nine ebselen derivatives (EBs) exhibited stronger inhibitory effect on Mpro with IC50 of 0.07-0.38 µM. Further evaluation of three derivatives showed that EB2-7 exhibited the most potent inhibition of SARS-CoV-2 viral replication with an IC50 value of 4.08 µM in HPAepiC cells, as compared to the prototype ebselen at 24.61 µM. Mechanistically, EB2-7 functions as a noncovalent Mpro inhibitor in LC-MS/MS assay. Taken together, our identification of ebselen derivatives with improved antiviral activity may lead to developmental potential for treatment of COVID-19 and SARS-CoV-2 infection.
Asunto(s)
Antivirales/química , Proteasas 3C de Coronavirus/química , Isoindoles/química , Compuestos de Organoselenio/química , SARS-CoV-2/enzimología , Antivirales/metabolismo , Antivirales/farmacología , Antivirales/uso terapéutico , Sitios de Unión , COVID-19/virología , Dominio Catalítico , Línea Celular , Supervivencia Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Proteasas 3C de Coronavirus/metabolismo , Diseño de Fármacos , Transferencia Resonante de Energía de Fluorescencia , Humanos , Isoindoles/metabolismo , Isoindoles/farmacología , Isoindoles/uso terapéutico , Simulación del Acoplamiento Molecular , Compuestos de Organoselenio/metabolismo , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/uso terapéutico , SARS-CoV-2/aislamiento & purificación , Relación Estructura-Actividad , Espectrometría de Masas en Tándem , Tratamiento Farmacológico de COVID-19RESUMEN
Among organic-inorganic hybrid molecules consisting of organic structure(s) and metal(s), only few studies are available on the cytotoxicity of nucleophilic molecules. In the present study, we investigated the cytotoxicity of a nucleophilic organotellurium compound, diphenyl ditelluride (DPDTe), using a cell culture system. DPDTe exhibited strong cytotoxicity against vascular endothelial cells and fibroblasts along with high intracellular accumulation but showed no cytotoxicity and had less accumulation in vascular smooth muscle cells and renal epithelial cells. The cytotoxicity of DPDTe decreased when intramolecular tellurium atoms were replaced with selenium or sulfur atoms. Electronic state analysis revealed that the electron density between tellurium atoms in DPDTe was much lower than those between selenium atoms of diphenyl diselenide and sulfur atoms of diphenyl disulfide. Moreover, diphenyl telluride did not accumulate and exhibit cytotoxicity. The cytotoxicity of DPDTe was also affected by substitution. p-Dimethoxy-DPDTe showed higher cytotoxicity, but p-dichloro-DPDTe and p-methyl-DPDTe showed lower cytotoxicity than that of DPDTe. The subcellular distribution of the compounds revealed that the compounds with stronger cytotoxicity showed higher accumulation rates in the mitochondria. Our findings suggest that the electronic state of tellurium atoms in DPDTe play an important role in accumulation and distribution of DPDTe in cultured cells. The present study supports the hypothesis that nucleophilic organometallic compounds, as well as electrophilic organometallic compounds, exhibit cytotoxicity by particular mechanisms.
Asunto(s)
Derivados del Benceno/farmacología , Células Endoteliales/efectos de los fármacos , Compuestos Organometálicos/farmacología , Compuestos de Organoselenio/farmacología , Telurio/farmacología , Animales , Derivados del Benceno/química , Derivados del Benceno/metabolismo , Bovinos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Células Endoteliales/citología , Células Endoteliales/metabolismo , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Humanos , Células LLC-PK1 , Modelos Químicos , Estructura Molecular , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Compuestos Organometálicos/química , Compuestos Organometálicos/metabolismo , Compuestos de Organoselenio/química , Compuestos de Organoselenio/metabolismo , Porcinos , Telurio/químicaRESUMEN
In this manuscript the ability of selenium carbohydrates to undergo chalcogen bonding (ChB) interactions with protein residues has been studied at the RI-MP2/def2-TZVP level of theory. An inspection of the Protein Data Bank (PDB) revealed SeA (A = O, C and S) intermolecular contacts involving Se-pyranose ligands and ASP, TYR, SER and MET residues. Theoretical models were built to analyse the strength and directionality of the interaction together with "Atoms in Molecules" (AIM), Natural Bonding Orbital (NBO) and Non Covalent Interactions plot (NCIplot) analyses, which further assisted in the characterization of the ChBs described herein. We expect that the results from this study will be useful to expand the current knowledge regarding biological ChBs as well as to increase the visibility of the interaction among the carbohydrate chemistry community.
Asunto(s)
Lectinas/metabolismo , Monosacáridos/metabolismo , Compuestos de Organoselenio/metabolismo , Agaricales/química , Aspergillus oryzae/química , Bases de Datos de Proteínas , Escherichia coli/química , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/metabolismo , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Enlace de Hidrógeno , Lectinas/química , Modelos Moleculares , Monosacáridos/química , Compuestos de Organoselenio/química , Unión Proteica , Selenio/química , Electricidad Estática , TermodinámicaRESUMEN
The COVID-19 pandemic caused by the SARS-CoV-2 has mobilized scientific attention in search of a treatment. The cysteine-proteases, main protease (Mpro) and papain-like protease (PLpro) are important targets for antiviral drugs. In this work, we simulate the interactions between the Mpro and PLpro with Ebselen, its metabolites and derivatives with the aim of finding molecules that can potentially inhibit these enzymes. The docking data demonstrate that there are two main interactions between the thiol (-SH) group of Cys (from the protease active sites) and the electrophilic centers of the organoselenium molecules, i. e. the interaction with the carbonyl group (O=C SH) and the interaction with the Se moiety (Se SH). Both interactions may lead to an adduct formation and enzyme inhibition. Density Functional Theory (DFT) calculations with Ebselen indicate that the energetics of the thiol nucleophilic attack is more favorable on Se than on the carbonyl group, which is in accordance with experimental data (Jin etâ al. Nature, 2020, 582, 289-293). Therefore, organoselenium molecules should be further explored as inhibitors of the SARS-CoV-2 proteases. Furthermore, we suggest that some metabolites of Ebselen (e. g. Ebselen diselenide and methylebselenoxide) and derivatives ethaselen and ebsulfur should be tested inâ vitro as inhibitors of virus replication and its proteases.
Asunto(s)
Azoles/farmacología , Tratamiento Farmacológico de COVID-19 , Proteasas Similares a la Papaína de Coronavirus/metabolismo , Compuestos de Organoselenio/farmacología , Inhibidores de Proteasas/farmacología , SARS-CoV-2/efectos de los fármacos , Proteínas de la Matriz Viral/metabolismo , Antivirales/química , Antivirales/metabolismo , Antivirales/farmacología , Azoles/química , Azoles/metabolismo , COVID-19/metabolismo , Dominio Catalítico/efectos de los fármacos , Proteasas Similares a la Papaína de Coronavirus/antagonistas & inhibidores , Descubrimiento de Drogas , Humanos , Isoindoles , Simulación del Acoplamiento Molecular , Compuestos de Organoselenio/química , Compuestos de Organoselenio/metabolismo , Inhibidores de Proteasas/química , Inhibidores de Proteasas/metabolismo , Proteínas de la Matriz Viral/antagonistas & inhibidoresRESUMEN
Selenium (Se) shows biologically ambivalent characteristics in animals. It is an essential element but becomes severely toxic when the amount ingested exceeds the adequate intake level. Animals must be able to metabolize the various selenocompounds in meat, fish and vegetables to utilize Se for selenoprotein synthesis. It is known that the biological, nutritional, and toxicological effects of Se are strongly dependent on its chemical form. First, we evaluated the nutritional availability of nine naturally occurring Se compounds, or the so-called bioselenocompounds, in vivo. Second, we evaluated that gut microflora might contributes to the Se nutritional availability. Se is mainly excreted into urine. However, a substantial amount of Se was secreted into bile although Se was hardly detected in feces. Third, we evaluated the biological significance of biliary secretion of Se in terms of mineral nutrition. Finally, we discussed the entire Se metabolism in gut contributing to Se homeostasis in animal.
Asunto(s)
Microbioma Gastrointestinal/fisiología , Compuestos de Selenio/metabolismo , Fenómenos Fisiológicos Nutricionales de los Animales/fisiología , Animales , Bilis/metabolismo , Glutatión/análogos & derivados , Glutatión/metabolismo , Células Hep G2 , Homeostasis , Humanos , Valor Nutritivo , Compuestos de Organoselenio/metabolismo , Ratas , Compuestos de Selenio/orinaRESUMEN
The emerging COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has raised a global catastrophe. To date, there is no specific antiviral drug available to combat this virus, except the vaccine. In this study, the main protease (Mpro) required for SARS-CoV-2 viral replication was expressed and purified. Thirty-six compounds were tested as inhibitors of SARS-CoV-2 Mpro by fluorescence resonance energy transfer (FRET) technique. The half-maximal inhibitory concentration (IC50) values of Ebselen and Ebsulfur analogs were obtained to be in the range of 0.074-0.91 µM. Notably, the molecules containing furane substituent displayed higher inhibition against Mpro, followed by Ebselen 1i (IC50 = 0.074 µM) and Ebsulfur 2k (IC50 = 0.11 µM). The action mechanism of 1i and 2k were characterized by enzyme kinetics, pre-incubation and jump dilution assays, as well as fluorescent labeling experiments, which suggested that both compounds covalently and irreversibly bind to Mpro, while molecular docking suggested that 2k formed an SS bond with the Cys145 at the enzymatic active site. This study provides two very potent scaffolds Ebsulfur and Ebselen for the development of covalent inhibitors of Mpro to combat COVID-19.
Asunto(s)
Antivirales/metabolismo , Azoles/metabolismo , Compuestos de Organoselenio/metabolismo , SARS-CoV-2/metabolismo , Compuestos de Azufre/metabolismo , Proteínas de la Matriz Viral/metabolismo , Antivirales/química , Antivirales/uso terapéutico , Azoles/química , Azoles/uso terapéutico , Sitios de Unión , COVID-19/patología , COVID-19/virología , Dominio Catalítico , Transferencia Resonante de Energía de Fluorescencia , Humanos , Concentración 50 Inhibidora , Isoindoles , Cinética , Simulación del Acoplamiento Molecular , Compuestos de Organoselenio/química , Compuestos de Organoselenio/uso terapéutico , SARS-CoV-2/aislamiento & purificación , Relación Estructura-Actividad , Compuestos de Azufre/química , Compuestos de Azufre/uso terapéutico , Proteínas de la Matriz Viral/antagonistas & inhibidores , Proteínas de la Matriz Viral/genética , Tratamiento Farmacológico de COVID-19RESUMEN
Although selenocysteine selenenic acids (Sec-SeOHs) have been recognized as key intermediates in the catalytic cycle of glutathione peroxidase (GPx), examples of the direct observation of Sec-SeOH in either protein or small-molecule systems have remained elusive so far, mostly due to their instability. Here, we report the first direct spectroscopic (1H and 77Se NMR) evidence for the formation of Sec-SeOH in small-molecule selenocysteine and selenopeptide model systems with a cradle-type protective group. The catalytic cycle of GPx was investigated using NMR-observable Sec-SeOH models. All the hitherto proposed chemical processes, i.e., not only those of the canonical catalytic cycle but also those involved in the bypass mechanism, including the intramolecular cyclization of Sec-SeOH to the corresponding five-membered ring selenenyl amide, were examined in a stepwise manner.
Asunto(s)
Ácidos Carboxílicos/química , Glutatión Peroxidasa/química , Compuestos de Organoselenio/química , Selenocisteína/química , Ácidos Carboxílicos/metabolismo , Catálisis , Cristalografía por Rayos X , Glutatión Peroxidasa/metabolismo , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular/métodos , Compuestos de Organoselenio/metabolismo , Selenocisteína/metabolismoRESUMEN
Cumulative evidence suggests that ß-amyloid and oxidative stress are closely related with each other and play key roles in the process of Alzheimer's disease (AD). Multitarget regulation of both pathways might represent a promising therapeutic strategy. Here, a series of selenium-containing compounds based on ebselen and verubecestat were designed and synthesized. Biological evaluation showed that 13f exhibited good BACE-1 inhibitory activity (IC50 = 1.06 µΜ) and potent GPx-like activity (ν0 = 183.0 µM min-1). Aß production experiment indicated that 13f could reduce the secretion of Aß1-40 in HEK APPswe 293T cells. Moreover, 13f exerted a cytoprotective effect against the H2O2 or 6-OHDA caused cell damage via alleviation of intracellular ROS, mitochondrial dysfunction, Ca2+ overload and cell apoptosis. The mechanism studies indicated that 13f exhibited cytoprotective effect by activating the Keap1-Nrf2-ARE pathway and stimulating downstream anti-oxidant protein including HO-1, NQO1, TrxR1, GCLC, and GCLM. In addition, 13f significantly reduced the production of NO and IL-6 induced by LPS in BV2 cells, which confirmed its anti-inflammatory activity as a Nrf2 activator. The BBB permeation assay predicted that 13f was able to cross the BBB. In summary, 13f might be a promising multi-target-directed ligand for the treatment of AD.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Ligandos , Factor 2 Relacionado con NF-E2/antagonistas & inhibidores , Fármacos Neuroprotectores/síntesis química , Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Antioxidantes/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Azoles/química , Azoles/metabolismo , Azoles/farmacología , Azoles/uso terapéutico , Sitios de Unión , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Óxidos S-Cíclicos/química , Óxidos S-Cíclicos/metabolismo , Óxidos S-Cíclicos/farmacología , Óxidos S-Cíclicos/uso terapéutico , Diseño de Fármacos , Humanos , Interleucina-6/metabolismo , Isoindoles , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Simulación del Acoplamiento Molecular , Factor 2 Relacionado con NF-E2/metabolismo , Fármacos Neuroprotectores/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Compuestos de Organoselenio/química , Compuestos de Organoselenio/metabolismo , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Fragmentos de Péptidos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Selenio/química , Transducción de Señal/efectos de los fármacos , Tiadiazinas/química , Tiadiazinas/metabolismo , Tiadiazinas/farmacología , Tiadiazinas/uso terapéuticoRESUMEN
Methylselenol (MeSeH) has been suggested to be a critical metabolite for anticancer activity of selenium, although the mechanisms underlying its activity remain to be fully established. The aim of this study was to identify metabolic pathways of MeSeH in Saccharomyces cerevisiae to decipher the mechanism of its toxicity. We first investigated in vitro the formation of MeSeH from methylseleninic acid (MSeA) or dimethyldiselenide. Determination of the equilibrium and rate constants of the reactions between glutathione (GSH) and these MeSeH precursors indicates that in the conditions that prevail in vivo, GSH can reduce the major part of MSeA or dimethyldiselenide into MeSeH. MeSeH can also be enzymatically produced by glutathione reductase or thioredoxin/thioredoxin reductase. Studies on the toxicity of MeSeH precursors (MSeA, dimethyldiselenide or a mixture of MSeA and GSH) in S.cerevisiae revealed that cytotoxicity and selenomethionine content were severely reduced in a met17 mutant devoid of O-acetylhomoserine sulfhydrylase. This suggests conversion of MeSeH into selenomethionine by this enzyme. Protein aggregation was observed in wild-type but not in met17 cells. Altogether, our findings support the view that MeSeH is toxic in S. cerevisiae because it is metabolized into selenomethionine which, in turn, induces toxic protein aggregation.
Asunto(s)
Metanol/análogos & derivados , Compuestos de Organoselenio/metabolismo , Agregación Patológica de Proteínas , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Metanol/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crecimiento & desarrollo , Proteínas de Saccharomyces cerevisiae/genéticaRESUMEN
mRNA-based therapies and vaccines constitute a disruptive technology with the potential to revolutionize modern medicine. Chemically modified 5' cap structures have provided access to mRNAs with superior translational properties that could benefit the currently flourishing mRNA field. Prime examples of compounds that enhance mRNA properties are antireverse cap analog diastereomers that contain an O-to-S substitution within the ß-phosphate (ß-S-ARCA D1 and D2), where D1 is used in clinically investigated mRNA vaccines. The compounds were previously found to have high affinity for eukaryotic translation initiation factor 4E (eIF4E) and augment translation in vitro and in vivo. However, the molecular basis for the beneficial "thio-effect" remains unclear. Here, we employed multiple biophysical techniques and captured 11 cap analog-eIF4E crystallographic structures to investigate the consequences of the ß-O-to-S or -Se substitution on the interaction with eIF4E. We determined the SP/RP configurations of ß-S-ARCA and related compounds and obtained structural insights into the binding. Unexpectedly, in both stereoisomers, the ß-S/Se atom occupies the same binding cavity between Lys162 and Arg157, indicating that the key driving force for complex stabilization is the interaction of negatively charged S/Se with positively charged amino acids. This was observed for all structural variants of the cap and required significantly different conformations of the triphosphate for each diastereomer. This finding explains why both ß-S-ARCA diastereomers have higher affinity for eIF4E than unmodified caps. Binding affinities determined for di-, tri-, and oligonucleotide cap analogs suggested that the "thio-effect" was preserved in longer RNAs. Our observations broaden the understanding of thiophosphate biochemistry and enable the rational design of translationally active mRNAs and eIF4E-targeting drugs.
Asunto(s)
Factor 4E Eucariótico de Iniciación/metabolismo , Oligonucleótidos Fosforotioatos/metabolismo , Caperuzas de ARN/metabolismo , Animales , Sitios de Unión , Línea Celular , Cristalografía por Rayos X , Factor 4E Eucariótico de Iniciación/química , Ratones , Conformación de Ácido Nucleico , Compuestos de Organoselenio/química , Compuestos de Organoselenio/metabolismo , Oligonucleótidos Fosforotioatos/química , Unión Proteica , Caperuzas de ARN/química , Electricidad Estática , EstereoisomerismoRESUMEN
BACKGROUND: Organocalcogens are a class of organic compounds obtained by the synthesis experiments to include S, Se, or Te. Among the elements that comprise this class, Se is characterized as an essential mineral and nutrient for humans. Se has been widely studied in many aspects. Organic synthesis of organoselenides is used for obtaining new potential drug candidates and may be highly beneficial from the use of computational approaches to reduce time and cost of the experiments. Thus, the goal of our study is to evaluate the computational approaches used in the organoselenides research from 1999 to 2019. METHODS: A literature review was performed by searching the database "Web of Sciences". RESULTS: Most of the theoretical studies included structural elucidation or structure-property analysis. We also found research regarding molecular docking approaches and Quantitative Structure-Activity Relationship (QSAR) studies. CONCLUSIONS: Computational studies have been widely applied to organoselenides. They demonstrated promising results and resulted in reduced the cost of research, increased efficacy, and, ultimately, novel organoselenides with desired properties.
Asunto(s)
Compuestos de Organoselenio/química , Diseño de Fármacos , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Monoaminooxidasa/química , Monoaminooxidasa/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Compuestos de Organoselenio/metabolismo , Compuestos de Organoselenio/uso terapéutico , Relación Estructura-Actividad CuantitativaRESUMEN
Organoselenium drugs like selenourea (SeU) and selenocystine (SeC) are found to exhibit several medicinal properties and have reported roles in the field of cancer prevention. However, studies related to their interactions with the major erythroid protein, haemoglobin (HbA) are still in dearth despite being of prime importance. In view of this, it was considered essential to investigate the interaction of these two anticancer drugs with Hb. Both the drugs showed significant changes in absorption spectra of Hb at wavelength of maximum absorption (λmax) 630 nm. SeU itself had no effect on the absorbance value at 630 nm with respect to time even with 400 µM concentration. However, it was rapidly converted to nanoselenium in presence of nitrite and there was an increase in the absorbance rate at 630 nm from 3.39 × 10-3 min-1 (without nitrite) to 8.94 × 10-3 min-1 in presence of nitrite (200 µM) owing to the generation of reactive oxygen species in the medium. Although the generation and increase in peak intensity at 630 nm in Hb generally indicates the formation and rise in the levels of methaemoglobin (metHb), nanoselenium was observed to follow a different path. Instead of causing oxidation of Fe2+ to Fe3+ responsible for metHb formation, nanoselenium was found to interact with the protein part, thereby causing changes in its secondary structure which is reflected in the increasing absorbance at 630 nm. SeC, however, showed a different effect. It was shown to act as a novel agent to reduce nitrite-induced metHb formation in a dose-dependent manner. The efficiency of SeC was again found to be less in diabetic blood samples as compared to the non-diabetic ones. For similar ratio of metHb to SeC (1:8), % reduction of metHb was found to be 27.46 ± 0.82 and 16.1 ± 2.4 for non-diabetic and diabetic samples, respectively, with a two tailed P-value much <0.05 which implies that the data are highly significant.
Asunto(s)
Cistina/análogos & derivados , Diabetes Mellitus/sangre , Hemoglobinas/metabolismo , Metahemoglobinemia/sangre , Compuestos de Organoselenio/farmacología , Urea/análogos & derivados , Anciano , Cistina/metabolismo , Cistina/farmacología , Diabetes Mellitus/metabolismo , Hemoglobinas/análisis , Humanos , Metahemoglobina/análisis , Metahemoglobina/metabolismo , Metahemoglobinemia/metabolismo , Persona de Mediana Edad , Nitritos/sangre , Compuestos de Organoselenio/metabolismo , Oxidación-Reducción , Especies Reactivas de Oxígeno , Urea/metabolismo , Urea/farmacologíaRESUMEN
Previously we have shown that among 15 substituted salicyloyl (2-hydroxybenzoyl) 5-seleninic acids (SSAs) 4 compounds with longer side chains or a cyclohexyl group exhibit no glutathione peroxidase (GPx)-like activity in the coupled reductase assay. Experimental inhibition of glutathione reductase (GR) by the selenenylsulfide (a main intermediate in the catalytic cycle for GPx-like activity determination) of one of the inactive compounds led us to assess the interactions between 15 selenenylsulfide compounds and the active site of GR by molecular docking. Docking results showed that S and Se atoms in selenenylsulfides of the compounds with no GPx-like activity were beyond 5â¯Å from S atom of Cys-58 or N atom of imidazole ring of His-467 (Root Mean Square Distances for general assessment of 3 major distances were over 4.8â¯Å) in the active site, so that they could not be catalyzed to be reduced by GR. Furthermore, their docking scores over 89 Kcal/mol meant that the selenenylsulfides were bound too strongly to the active site to leave it, leading eventually to inhibition of GR. We also applied the molecular docking to other GPx mimics such as ebselen, cyclic seleninate esters and di(propylaminomethylphenyl) diselenides to explain the differences in their GPx-like activity depending to the assays used. Our results suggest that the reduction of a selenenylsulfide by GR plays a positive role in GPx-like activity of GPx mimics in the coupled assay and recommended the prediction of possibility and strength of GPx-like activity by molecular docking before entering experimental research.
Asunto(s)
Ácidos Carboxílicos/metabolismo , Glutatión Peroxidasa/metabolismo , Glutatión Reductasa/metabolismo , Compuestos de Organoselenio/metabolismo , Antioxidantes/metabolismo , Ácidos Carboxílicos/química , Catálisis , Glutatión/química , Glutatión/metabolismo , Isoindoles/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Compuestos de Organoselenio/químicaRESUMEN
Coronaviruses represent global health threat. In this century, they have already caused two epidemics and one serious pandemic. Although, at present, there are no approved drugs and therapies for the treatment and prevention of human coronaviruses, several agents, FDA-approved, and preclinical, have shown in vitro and/or in vivo antiviral activity. An in-depth analysis of the current situation leads to the identification of several potential drugs that could have an impact on the fight against coronaviruses infections. In this review, we discuss the virology of human coronaviruses highlighting the main biological targets and summarize the current state-of-the-art of possible therapeutic options to inhibit coronaviruses infections. We mostly focus on FDA-approved and preclinical drugs targeting viral conserved elements.
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Enzima Convertidora de Angiotensina 2/metabolismo , COVID-19/metabolismo , Infecciones por Coronavirus/metabolismo , Coronavirus/metabolismo , Dipeptidil Peptidasa 4/metabolismo , Síndrome Respiratorio Agudo Grave/metabolismo , Enzima Convertidora de Angiotensina 2/antagonistas & inhibidores , Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Inhibidores de la Enzima Convertidora de Angiotensina/metabolismo , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/metabolismo , Antivirales/administración & dosificación , Antivirales/metabolismo , Azoles/administración & dosificación , Azoles/metabolismo , Coronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/metabolismo , Humanos , Isoindoles , Naftoquinonas/administración & dosificación , Naftoquinonas/metabolismo , Compuestos de Organoselenio/administración & dosificación , Compuestos de Organoselenio/metabolismo , Síndrome Respiratorio Agudo Grave/tratamiento farmacológico , Tratamiento Farmacológico de COVID-19RESUMEN
Low molecular weight selenium containing metabolites in the leaves of the selenium hyperaccumulator Cardamine violifolia (261 mg total Se per kg d.w.) were targeted in this study. One dimensional cation exchange chromatography coupled to ICP-MS was used for purification and fractionation purposes prior to LC-Unispray-QTOF-MS analysis. The search for selenium species in full scan spectra was assisted with an automated mass defect based filtering approach. Besides selenocystathionine, selenohomocystine and its polyselenide derivative, a total number of 35 water soluble selenium metabolites other than selenolanthionine were encountered, including 30 previously unreported compounds. High occurrence of selenium containing hexoses was observed, together with the first assignment of N-glycoside derivatives of selenolanthionine. Quantification of the most abundant selenium species, selenolanthionine, was carried out with an ion pairing LC - post column isotope dilution ICP-MS setup, which revealed that this selenoamino acid accounted for 30% of the total selenium content of the leaf (78 mg (as Se) per kg d.w.).
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Cardamine/metabolismo , Cistationina/análogos & derivados , Homocistina/análogos & derivados , Compuestos de Organoselenio/metabolismo , Selenio/metabolismo , Alanina/análogos & derivados , Alanina/análisis , Alanina/metabolismo , Cardamine/química , Cistationina/análisis , Cistationina/metabolismo , Homocistina/análisis , Homocistina/metabolismo , Compuestos de Organoselenio/análisis , Hojas de la Planta/química , Hojas de la Planta/metabolismo , Selenio/análisis , Solubilidad , Agua/químicaRESUMEN
Inositol monophosphatase (IMPase) is inhibited by lithium, which is the most efficacious treatment for bipolar disorder. Several therapies have been approved, or are going through clinical trials, aimed at the replacement of lithium in the treatment of bipolar disorder. One candidate small molecule is ebselen, a selenium-containing antioxidant, which has been demonstrated to produce lithium-like effects both in a murine model and in clinical trials. Here, the crystallization and the first structure of human IMPase covalently complexed with ebselen, a 1.47â Å resolution crystal structure (PDB entry 6zk0), are presented. In the complex with human IMPase, ebselen in a ring-opened conformation is covalently attached to Cys141, a residue located away from the active site. IMPase is a dimeric enzyme and in the crystal structure two adjacent dimers share four ebselen molecules, creating a tetramer with approximate 222 symmetry. In the crystal structure presented in this publication, the active site in the tetramer is still accessible, suggesting that ebselen may function as an allosteric inhibitor or may block the binding of partner proteins.
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Antioxidantes/metabolismo , Azoles/metabolismo , Cristalografía por Rayos X/métodos , Cisteína/metabolismo , Compuestos de Organoselenio/metabolismo , Ubiquitina-Proteína Ligasas/química , Ubiquitina-Proteína Ligasas/metabolismo , Cisteína/química , Humanos , Isoindoles , Unión Proteica , Conformación Proteica , Dominios ProteicosRESUMEN
A series of organoselenium compounds based on the hybridization of nonsteroidal antiinflammatory drugs (NSAIDs) scaffolds and Se functionalities (-SeCN and -SeCF3) were synthesized and characterized, and evaluated against four types of cancer cell lines, SW480 (human colon adenocarcinoma cells), HeLa (human cervical cancer cells), A549 (human lung carcinoma cells), MCF-7 (human breast adenocarcinoma cells). Interestingly, most of the investigated compounds showed active in reducing the viability of different cancer cell lines. The most active compound 3h showed IC50 values lower than 20 µM against the four cancer cell lines, particularly to SW480 and MCF-7 with IC 50 values of 4.9 and 3.4 µM, respectively. Furthermore, NSAIDs-SeCN derivatives (2h and 2i) and NSAIDs-SeCF3 derivatives (3h and 3i) were selected to investigate their ability to induce apoptosis in MCF-7 cells via modulation the expression of anti-apoptotic Bcl-2 protein, pro-inflammatory cytokines (IL-2) and proapoptotic caspase-3 protein. Moreover, the redox properties of the synthesized organoselenium candidates were conducted by 2, 2-didiphenyl-1-picrylhydrazyl (DPPH), bleomycin dependent DNA damage and glutathione peroxidase (GPx)-like assays. Taken together, these NSAIDs-Se candidates could provide promising new lead derivatives for further potential anticancer drug development.
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Antiinflamatorios no Esteroideos/farmacología , Antineoplásicos/farmacología , Compuestos de Organoselenio/farmacología , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/metabolismo , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Línea Celular Tumoral , ADN/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Depuradores de Radicales Libres/síntesis química , Depuradores de Radicales Libres/metabolismo , Depuradores de Radicales Libres/farmacología , Humanos , Interleucina-2/metabolismo , Simulación del Acoplamiento Molecular , Compuestos de Organoselenio/síntesis química , Compuestos de Organoselenio/metabolismo , Unión Proteica , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Tiorredoxina Reductasa 1/metabolismoRESUMEN
There is an urgent need to repurpose drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent computational-experimental screenings have identified several existing drugs that could serve as effective inhibitors of the virus' main protease, Mpro, which is involved in gene expression and replication. Among these, ebselen (2-phenyl-1,2-benzoselenazol-3-one) appears to be particularly promising. Here, we examine, at a molecular level, the potential of ebselen to decrease Mpro activity. We find that it exhibits a distinct affinity for the catalytic region. Our results reveal a higher-affinity, previously unknown binding site localized between the II and III domains of the protein. A detailed strain analysis indicates that, on such a site, ebselen exerts a pronounced allosteric effect that regulates catalytic site access through surface-loop interactions, thereby inducing a reconfiguration of water hotspots. Together, these findings highlight the promise of ebselen as a repurposed drug against SARS-CoV-2.