RESUMO
Antiretrovirals have improved considerably since the introduction of 3'-azido-3'-deoxythymidine (zidovudine or AZT), a molecule with also anticancer effects. Subsequently, a variety of other nucleosides have been synthesized. However, these medications are often associated with serious adverse events and the onset or exacerbation of degenerative processes, diseases, and syndromes, affecting mainly the mitochondria. In this study, we used Caenorhabditis elegans to investigate the toxicity potential of AZT and three new organoselenium derivatives with modifications in the 5' position of the sugar ring in place of the 5'-OH group, with the insertion of a neutral, an electron-withdrawing and an electron-donating group attached to the aryl selenol moiety: 5'-seleno-(4-chloro-phenyl)-3-(amino)-thymidine (ASAT-4-Cl), 5'-seleno-(phenyl)-3-(amino)-thymidine (ASAT-Ph), and 5'-seleno-(4-methoxyphenyl)-3-(amino)- thymidine (ASAT-4-OMe). Analyzes included worm survival, behavior parameters, high-resolution respirometry, citrate synthase activity, and ATP levels. Although all compounds negatively affected C. elegans, ASAT-4-Cl and ASAT-Ph showed lower toxicity compared to AZT, especially in mitochondrial viability and ATP production. Therefore, more studies must be carried out on the use of these new compounds as pharmacological interventions.
Assuntos
Caenorhabditis elegans , Compostos Organosselênicos , Zidovudina , Animais , Caenorhabditis elegans/efeitos dos fármacos , Zidovudina/toxicidade , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/toxicidade , Mitocôndrias/efeitos dos fármacos , Fármacos Anti-HIV/toxicidadeRESUMO
We present our results on the synthesis and preliminary in silico and inâ vitro studies of the toxicology and antioxidant properties of selenylated analogs of Tacrine. Initially, we synthesized 2-aminobenzonitriles containing an organic selenium moiety, resulting in sixteen compounds with various substituents linked to the portion derived from diorganyl diselenide. These compounds were then used as substrates in reactions with cyclic ketones, in the presence of 1.4 equivalents of trifluoroboroetherate as a Lewis acid, to synthesize selenylated analogs of Tacrine with yields ranging from 20 % to 87 %. In silico studies explored computational parameters related to antioxidant activity and hepatotoxicity. In vitro studies elucidated the antioxidant effects of Tacrine and its selenium hybrid (TSe) in neutralizing ABTS radicals, scavenging DPPH radicals, and reducing iron ions. Additionally, the acute oral toxicity of one synthesized compound was evaluated.
Assuntos
Antioxidantes , Compostos de Bifenilo , Picratos , Tacrina , Antioxidantes/química , Antioxidantes/farmacologia , Antioxidantes/síntese química , Tacrina/química , Tacrina/farmacologia , Tacrina/síntese química , Animais , Picratos/antagonistas & inibidores , Picratos/química , Compostos de Bifenilo/antagonistas & inibidores , Compostos de Bifenilo/química , Estrutura Molecular , Ratos , Masculino , Benzotiazóis/química , Benzotiazóis/síntese química , Simulação por Computador , Ácidos Sulfônicos/química , Ácidos Sulfônicos/antagonistas & inibidores , Compostos Organosselênicos/química , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/síntese química , Compostos Organosselênicos/toxicidadeRESUMO
Here, we addressed the pharmacology and toxicology of synthetic organoselenium compounds and some naturally occurring organoselenium amino acids. The use of selenium as a tool in organic synthesis and as a pharmacological agent goes back to the middle of the nineteenth and the beginning of the twentieth centuries. The rediscovery of ebselen and its investigation in clinical trials have motivated the search for new organoselenium molecules with pharmacological properties. Although ebselen and diselenides have some overlapping pharmacological properties, their molecular targets are not identical. However, they have similar anti-inflammatory and antioxidant activities, possibly, via activation of transcription factors, regulating the expression of antioxidant genes. In short, our knowledge about the pharmacological properties of simple organoselenium compounds is still elusive. However, contrary to our early expectations that they could imitate selenoproteins, organoselenium compounds seem to have non-specific modulatory activation of antioxidant pathways and specific inhibitory effects in some thiol-containing proteins. The thiol-oxidizing properties of organoselenium compounds are considered the molecular basis of their chronic toxicity; however, the acute use of organoselenium compounds as inhibitors of specific thiol-containing enzymes can be of therapeutic significance. In summary, the outcomes of the clinical trials of ebselen as a mimetic of lithium or as an inhibitor of SARS-CoV-2 proteases will be important to the field of organoselenium synthesis. The development of computational techniques that could predict rational modifications in the structure of organoselenium compounds to increase their specificity is required to construct a library of thiol-modifying agents with selectivity toward specific target proteins.
Assuntos
Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/toxicidade , Aminoácidos/química , Animais , Azóis , Humanos , Isoindóis , Estrutura Molecular , Selênio/química , Selênio/fisiologia , Selenoproteínas/química , Compostos de Sulfidrila/químicaRESUMO
BACKGROUND AND OBJECTIVE: Evidence point out promising anticancer activities of Dihydropyrimidinones (DHPM) and organoselenium compounds. This study aimed to evaluate the cytotoxic and antiproliferative potential of DHPM-derived selenoesters (Se-DHPM), as well as their molecular mechanisms of action. METHODS: Se-DHPM cytotoxicity was evaluated against cancer lines (HeLa, HepG2, and MCF-7) and normal cells (McCoy). HepG2 clonogenic assay allowed verifying antiproliferative effects. The propidium iodide/ orange acridine fluorescence readings showed the type of cell death induced after treatments (72h). Molecular simulations with B-DNA and 49H showed docked positions (AutoDock Vina) and trajectories/energies (GROMACS). In vitro molecular interactions used CT-DNA and 49H applying UV-Vis absorbance and fluorescence. Comet assay evaluated DNA fragmentation of HepG2 cells. Flow cytometry analysis verified HepG2 cell cycle effects. Levels of proteins (ß-actin, p53, BAX, HIF-1α, γH2AX, PARP-1, cyclin A, CDK-2, and pRB) were quantified by immunoblotting. RESULTS: Among Se-DHPM, 49H was selectively cytotoxic to HepG2 cells, reduced cell proliferation, and increased BAX (80%), and p53 (66%) causing apoptosis. Molecular assays revealed 49H inserted in the CT-DNA molecule causing the hypochromic effect. Docking simulations showed H-bonds and hydrophobic interactions, which kept the ligand partially inserted into the DNA minor groove. 49H increased the DNA damage (1.5 fold) and γH2AX level (153%). Besides, treatments reduced PARP-1 (60%) and reduced pRB phosphorylation (21%) as well as decreased cyclin A (46%) arresting cell cycle at the G1 phase. CONCLUSION: Together all data obtained confirmed the hypothesis of disruptive interactions between Se-DHPM and DNA, thereby highlighting its potential as a new anticancer drug.
Assuntos
Antineoplásicos/síntese química , Carcinoma Hepatocelular/tratamento farmacológico , Citotoxinas/síntese química , Neoplasias Hepáticas/tratamento farmacológico , Compostos Organosselênicos/síntese química , Actinina/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citotoxinas/farmacologia , Fragmentação do DNA/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Simulação de Acoplamento Molecular , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/toxicidade , Fosforilação , Relação Estrutura-Atividade , Proteína X Associada a bcl-2/metabolismoRESUMO
This article provides a comprehensive overview of reported methods - particularly copper- and organocatalyzed reactions - for the regioselective syntheses of selenium-containing 1,2,3-triazoles systems. These chemical entities are prevalent cores in biologically active compounds and functional materials. In view of their unique properties, substantial efforts have been paid for the design and development of practical approaches for the synthesis of these scaffolds.
Assuntos
Cobre/química , Compostos Organosselênicos/síntese química , Triazóis/síntese química , Catálise , Linhagem Celular Tumoral , Química Click , Reação de Cicloadição , Humanos , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/toxicidade , Triazóis/farmacologia , Triazóis/toxicidadeRESUMO
Organoselenium compounds have been targeted to new therapeutic tools development due to their pharmacological actions. However, some toxicity issues and physicochemical limitations delay the clinical application of these compounds. The incorporation of organoselenium molecules into nanostructured systems arises as a promising alternative to overcome such restrictions. The current study proposed the characterization of the polymeric nanocapsules of p,p'-methoxyl-diphenyl diselenide [(OMePhSe)2] as well as the evaluation of the in vivo toxicity and biodistribution profile. The nanocapsules, which were composed by medium-chain triglycerides as the oil core and poly(ε-caprolactone) as the polymeric wall, showed nanometric size (236±4), low polydispersity (<0.2), negative zeta potential (-5.4±0.06), neutral pH values (7.2±0.08) and a high encapsulation efficiency (98%). Besides, the nanoencapsulation process increased the (OMePhSe)2 stability. The repeated intragastric administration of (OMePhSe)2 nanoencapsulated (25mg/kg/day during 7days) did not cause any alteration in the oxidative status, hematological parameters, and plasma biochemical markers of cellular damage. Moreover, the (OMePhSe)2 incorporation into nanocapsules increased the selenium concentrations in the tissues (kidneys, liver and plasma) suggesting an improvement in its oral bioavailability.
Assuntos
Portadores de Fármacos/química , Nanocápsulas/química , Compostos Organosselênicos/química , Polímeros/química , Animais , Portadores de Fármacos/toxicidade , Estabilidade de Medicamentos , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Masculino , Camundongos , Nanocápsulas/toxicidade , Compostos Organosselênicos/toxicidade , Polímeros/toxicidade , Distribuição Tecidual/efeitos dos fármacos , Distribuição Tecidual/fisiologia , Testes de Toxicidade Aguda/métodosRESUMO
Organoselenium compounds and isoquinoline derivatives have their toxicity linked to induction of pro-oxidant situations. δ-Aminolevulinate dehydratase (δ-ALA-D) and Na+ , K+ -ATPase have sulfhydryl groups susceptible to oxidation. Thus, we investigated toxicological effects of 4-organoseleno-isoquinoline derivatives, cerebral monoamine oxidase B inhibitors, on rat cerebral δ-ALA-D and Na+ , K+ -ATPase activities and the involvement of sulfhydryl groups in vitro. Compounds substituted with fluoro (4-(4-fluorophenylseleno)-3-phenylisoquinoline), chloro (4-(4-chlorophenylseleno)-3-phenylisoquinoline) and trifluoro (4-(3-trifluoromethylphenylseleno)-3-phenylisoquinoline) at the selenium-bonded aromatic ring inhibited δ-ALA-D (IC50 values: 78.42, 92.27, 44.98 µM) and Na+ , K+ -ATPase (IC50 values: 41.36, 89.43, 50.66 µM) activities, possibly due to electronic effects induced by these groups. 3-Phenyl-4-(phenylseleno) isoquinoline (without substitution at the selenium-bonded aromatic ring) and 4-(4-methylphenylseleno)-3-phenylisoquinoline (with a methyl group substituted at the selenium-bonded aromatic ring) did not alter the activity of these enzymes. Dithiothreitol, a reducing agent, restored the enzymatic activities inhibited by 4-(4-fluorophenylseleno)-3-phenylisoquinoline, 4-(4-chlorophenylseleno)-3-phenylisoquinoline and 4-(3-trifluoromethylphenylseleno)-3-phenylisoquinoline, suggesting the involvement of sulfhydryl residues in this effect. However, the release of essential zinc seems not to be related to the δ-ALA-D inhibition by these compounds. According to these data, the effect of oral administration (300 mg/kg, intragastric) of 3-phenyl-4-(phenylseleno) isoquinoline on markers of systemic toxicity in Wistar rats was evaluated. None signs of toxicity was observed during or after treatment. This study suggests that the insertion of electron-withdrawing groups in the aromatic ring bonded to the selenium atom of isoquinolines tested increased its inhibitory effect on sulfhydryl enzymes in vitro. 3-Phenyl-4-(phenylseleno) isoquinoline, which has documented pharmacological properties, had no toxicological effects on the parameters evaluated in this study. J. Cell. Biochem. 118: 1144-1150, 2017. © 2016 Wiley Periodicals, Inc.
Assuntos
Isoquinolinas/toxicidade , Compostos Organosselênicos/toxicidade , Sintase do Porfobilinogênio/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Compostos de Sulfidrila/toxicidade , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Cloretos/farmacologia , Ditiotreitol/farmacologia , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Feminino , Isoquinolinas/química , Masculino , Compostos Organosselênicos/química , Sintase do Porfobilinogênio/antagonistas & inibidores , Ratos , Ratos Wistar , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Compostos de Sulfidrila/química , Testes de Toxicidade , Compostos de Zinco/farmacologiaRESUMO
A growing body of evidence demonstrates that quinoline compounds have attracted much attention in the field of drug development. Accordingly, 4-phenylselenyl-7-chloroquinoline (4-PSQ) is a new quinoline derivative containing selenium, which showed a potential antioxidant, antinociceptive and anti-inflammatory effect. The present study was undertaken to evaluate the anxiolytic-like properties of 4-PSQ. Mice were orally pretreated with 4-PSQ (5-50 mg/kg) or vehicle, 30 min prior to the elevated plus-maze (EPM), light-dark (LDT) or open field (OFT) tests. A time-response curve was carried out by administration of 4-PSQ (50 mg/kg) at different times before the EPM test. The involvement of glutamate uptake/release and Na+, K+-ATPase activity in the anxiolytic-like effect was investigated in cerebral cortices. In addition, the effectiveness of acute treatment with 4-PSQ was evaluated in a model of kainate (KA)-induced anxiety-related behavior. Finally, acute toxicity of this compound was investigated. 4-PSQ produced an anxiolytic-like action, both in EPM and LDT. In OFT, 4-PSQ did not affect locomotor and exploratory activities. 4-PSQ anxiolytic-like effect started at 0.5 h and remained significant up to 72 h after administration. Treatment with 4-PSQ reduced [3H] glutamate uptake, but the [3H] glutamate release and Na+, K+-ATPase activity were not altered. KA-induced anxiety-related behavior was protected by 4-PSQ pretreatment. Additionally, 4-PSQ exposure did not alter urea levels, aspartate (AST) and alanine aminotrasferase (ALT) activities in plasma. Parameters of oxidative stress in brain and liver of mice were not modified by 4-PSQ. Taken together these data demonstrated that the anxiolytic-like effect caused by 4-PSQ seems to be mediated by involvement of the glutamatergic system.
Assuntos
Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Fármacos Atuantes sobre Aminoácidos Excitatórios/farmacologia , Compostos Organosselênicos/farmacologia , Quinolinas/farmacologia , Administração Oral , Animais , Ansiolíticos/química , Ansiolíticos/toxicidade , Ansiedade/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Fármacos Atuantes sobre Aminoácidos Excitatórios/química , Fármacos Atuantes sobre Aminoácidos Excitatórios/toxicidade , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Ácido Glutâmico/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Compostos Organosselênicos/química , Compostos Organosselênicos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Testes Psicológicos , Quinolinas/química , Quinolinas/toxicidade , ATPase Trocadora de Sódio-Potássio/metabolismo , Fatores de Tempo , TrítioRESUMO
Acquired immunodeficiency syndrome (AIDS) is a worldwide disease characterized by impairments of immune function. AIDS can be associated with oxidative stress (OS) that can be linked to selenium (Se) deficiency. Se is fundamental for the synthesis of selenoproteins, such as glutathione peroxidase and thioredoxin reductase. These enzymes catalyze the decomposition of reactive oxygen species and contribute to maintain equilibrium in cell redox status. Literature data indicate that organoselenium compounds, such as ebselen and diphenyl diselenide, have antioxidant properties in vitro and in vivo models associated with OS. Nevertheless, selenocompounds can also react and oxidize thiols groups, inducing toxicity in mammals. Here, we tested the potential cytotoxic and genotoxic properties of six analogs of the prototypal anti-HIV drug azidothymidine (AZT) containing Se (5'-Se-(phenyl)zidovudine; 5'-Se-(1,3,5-trimethylphenyl)zidovudine; 5'-Se-(1-naphtyl)zidovudine; 5'-Se-(4-chlorophenyl)zidovudine) (C4); 5'-Se-(4-methylphenyl)zidovudine (C5); and 5'-(4-methylbenzoselenoate)zidovudine). C5 increased the rate of dithiothreitol oxidation (thiol oxidase activity) and C2-C4 and C6 (at 100 µM) increased DNA damage index (DI) in human leukocytes. Moreover, C5 (200 µM) decreased human leukocyte viability to about 50%. Taken together, these results indicated the low in vitro toxicity in human leukocytes of some Se-containing analogs of AZT.
Assuntos
Fármacos Anti-HIV/toxicidade , Leucócitos/efeitos dos fármacos , Compostos Organosselênicos/toxicidade , Zidovudina/análogos & derivados , Zidovudina/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ensaio Cometa , Dano ao DNA , HumanosRESUMO
The development of new drugs to treat painful and inflammatory clinical conditions continues to be of great interest. The present study evaluated the antinociceptive and anti-inflammatory effects of 4-phenylselenyl-7-chloroquinoline (4-PSQ). Mice were orally (p.o.) pretreated with 4-PSQ (0.1-25mg/kg), meloxicam (25mg/kg, a reference drug) or vehicle, 30min prior to the acetic acid, formalin, hot-plate and open-field tests. 4-PSQ reduced abdominal writhing induced by acetic acid and it caused an increase in latency time in the hot-plate test. 4-PSQ inhibited early and late phases of nociception and reduced the paw edema caused by formalin. Locomotor and exploratory activities in the open field test were not altered by treatments. In addition, a time-response curve was carried out by administration of 4-PSQ (25mg/kg; p.o.) at different times before the acetic acid injection. The antinociceptive effect in inhibiting acetic acid-induced abdominal writhing of 4-PSQ started at 0.5h and remained significant up to 4h after administration. Indeed, the anti-inflammatory and antioxidant properties of 4-PSQ were investigated. 4-PSQ diminished the edema formation and decreased the myeloperoxidase activity and reactive species levels induced by croton oil in the ear tissue. 4-PSQ partially protected against the decrease of the 2,2'-Azinobis-3-ethylbenzothiazoline 6-sulfonic acid (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) levels induced by croton oil. Meloxicam presented similar results for 4-PSQ in tests evaluated. These results demonstrated that 4-PSQ exerts acute anti-inflammatory and antinociceptive actions, suggesting that it may represent an alternative in the development of future new therapeutic strategies.
Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Compostos Organosselênicos/farmacologia , Quinolinas/farmacologia , Analgésicos/metabolismo , Analgésicos/uso terapêutico , Analgésicos/toxicidade , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/toxicidade , Comportamento Animal/efeitos dos fármacos , Benzotiazóis/metabolismo , Compostos de Bifenilo/metabolismo , Edema/tratamento farmacológico , Masculino , Camundongos , Compostos Organosselênicos/metabolismo , Compostos Organosselênicos/uso terapêutico , Compostos Organosselênicos/toxicidade , Peroxidase/metabolismo , Picratos/metabolismo , Quinolinas/metabolismo , Quinolinas/uso terapêutico , Quinolinas/toxicidade , Ácidos Sulfônicos/metabolismoRESUMO
Selenium is an essential micronutrient with several biological roles in the human body, but supra nutritional consumption can cause toxic effects. The potential deleterious effects of organoselenium compounds are controversial. The compound α-(phenylselanyl) acetophenone (PSAP) exhibits antioxidant, antidepressant-like and glutathione peroxidase-like activity, which makes important the elucidation of any toxic effects. Hence, the present study aims to investigate the in vitro toxicity of PSAP in Chinese Hamster ovary cells (through MTT assay) and analyse its genotoxicity using the comet assay in mice leukocytes after acute or chronic treatments, alongside with biochemical analyses. Our results demonstrate that the oral administration of PSAP in acute (1, 5, 10, 50, 200 mg/kg) and chronic (1, 10, 50, 200 mg/kg) doses did not cause genotoxicity. The compound presented cytotoxic effect in the MTT assay just at 500 µM after 24 h of administration and at 250 and 500 µM after 48 and 72 h of administration. According to biochemical analysis, PSAP presented a minor toxic effect by altering δ-ALA-D activity in liver and catalase activity in kidney at the highest tested concentration. Taking together, these data indicate that PSAP has low toxic effects after chronic administration in mice.
Assuntos
Acetofenonas/toxicidade , Antidepressivos/toxicidade , Antioxidantes/toxicidade , Compostos Organosselênicos/toxicidade , Acetofenonas/administração & dosagem , Administração Oral , Animais , Antidepressivos/administração & dosagem , Antioxidantes/administração & dosagem , Células CHO , Catalase , Sobrevivência Celular/efeitos dos fármacos , Ensaio Cometa , Cricetulus , Dano ao DNA , Relação Dose-Resposta a Droga , Esquema de Medicação , Rim/efeitos dos fármacos , Rim/enzimologia , Leucócitos/efeitos dos fármacos , Leucócitos/patologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Camundongos , Compostos Organosselênicos/administração & dosagem , Sintase do Porfobilinogênio/metabolismo , Medição de RiscoRESUMO
The organoselenium compounds have been reported for many biological properties, especially as potent antioxidants. The compound bis(phenylimidazoselenazolyl) diselenide (BPIS) is a novel diaryl diselenide derivative, which shows antinociceptive and anti-inflammatory properties in mice, but whose antioxidant activity has not been studied. The present study aimed to investigate the antioxidant and toxicological potential of BPIS in brain of rats in vitro, and the effect of BPIS against the oxidative damage induced by sodium nitroprusside (SNP) in mouse brain. BPIS, at low molecular range, reduced lipid peroxidation (LP) and protein carbonyl (PC) content in rat brain homogenates (IC50 values of 1.35 and 0.74 µM, respectively). BPIS also presented dehydroascorbate reductase-like and glutathione-S-transferase-like, as well as DPPH and NO-scavenging activities. Related to togicological assays, BPIS inhibited δ-ALA-D and Na(+), K(+)-ATPase activities in rat brain homogenates and [(3)H]glutamate uptake in synaptosomes in vitro, but these effects were observed at higher concentrations than it had antioxidant effect (IC50 values of 16.41, 26.44 and 3.29 µM, respectively). In vivo, brains of mice treated with SNP (0.335 µmol per site; i.c.v.) showed an increase in LP and PC and a reduction in non protein thiol content, however, it was not observed significant alterations in antioxidant enzyme activities. BPIS (10 mg/kg; p.o.) protected against these alterations caused by SNP. In conclusion, the results demonstrated the antioxidant action of BPIS in in vitro assays. Furthermore, BPIS protected against oxidative damage caused by SNP in mouse brain, strengthening the potential antioxidant effect of this compound.
Assuntos
Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ácido Aminolevulínico/metabolismo , Animais , Antioxidantes/toxicidade , Encéfalo/metabolismo , Encéfalo/patologia , Glutationa Transferase/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Óxido Nítrico/metabolismo , Compostos Organosselênicos/toxicidade , Carbonilação Proteica/efeitos dos fármacos , Ratos , Ratos Wistar , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
In this study, the antioxidant and antidepressant-like activities of the semi-synthetic compound α-phenylseleno citronellal (PhSeCIT) and the natural terpenoid R-citronellal (CIT) were evaluated. The biological potential of PhSeCIT and CIT was evaluated by antioxidant in vitro assays, such as 1,1-diphenyl-2-picryl-hydrazyl (DPPH), 2,2-azinobis(3-ethylbenzothiazoline-6-sulfonate) (ABTS), ferric ion reducing antioxidant power (FRAP) and linoleic acid oxidation. The compounds were also assessed by ex vivo tests to determine the acute toxicity, levels of thiobarbituric acid reactive species (TBARS), δ-aminolevulinate dehydratase (δ-Ala-D) and Na(+)/K(+) ATPase activities. The antidepressant-like activity of compounds in the tail suspension test (TST) and forced swimming test (FST) was also investigated. The results demonstrated that the addition of an organoselenium group to (R)-citronellal increased its antioxidant properties, since PhSeCIT showed better activity than CIT. The treatment of mice with both compounds did not cause death of any animals. The levels of TBARS were significantly reduced by PhSeCIT in liver and cortex of animals, whereas CIT did not alter these parameters. In the TST and FST, PhSeCIT showed promising antidepressant-like activity, while CIT was not active in this test. Taken together, these data demonstrate the role of selenium in the antioxidant and antidepressant-like activities of (R)-citronellal.
Assuntos
Aldeídos/farmacologia , Antidepressivos/farmacologia , Antioxidantes/farmacologia , Monoterpenos/farmacologia , Compostos Organosselênicos/farmacologia , Monoterpenos Acíclicos , Aldeídos/química , Aldeídos/toxicidade , Animais , Antidepressivos/química , Antidepressivos/toxicidade , Antioxidantes/química , Antioxidantes/toxicidade , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Ácido Linoleico/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Monoterpenos/química , Monoterpenos/toxicidade , Atividade Motora/efeitos dos fármacos , Compostos Organosselênicos/química , Compostos Organosselênicos/toxicidade , Plantas Medicinais , Sintase do Porfobilinogênio/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
The mechanisms that lead to the onset of organoselenium intoxication are still poorly understood. Therefore, in the present study, we investigated the effect of acute administration of 3-methyl-1-phenyl-2-(phenylseleno)oct-2-en-1-one on some parameters of oxidative stress and on the activity of creatine kinase (CK) in different brain areas and on the behaviour in the open field test of 90-day-old male rats. Animals (n = 10/group) were treated intraperitoneally with a single dose of the organoselenium (125, 250 or 500 µg kg(-1) ), and after 1 h of the drug administration, they were exposed to the open field test, and behaviour parameters were recorded. Immediately after they were euthanized, cerebral cortex, hippocampus and cerebellum were dissected for measurement of thiobarbituric acid reactive substances (TBARS), carbonyl, sulfhydryl, catalase (CAT), superoxide dismutase (SOD) and CK activity. Our results showed that the dose of 500 µg kg(-1) of the organoselenium increased the locomotion and rearing behaviours in the open field test. Moreover, the organochalcogen enhanced TBARS in the cerebral cortex and cerebellum and increased the oxidation of proteins (carbonyl) only in the cerebral cortex. Sulfhydryl content was reduced in all brain areas, CAT activity enhanced in the hippocampus and reduced in the cerebellum and SOD activity increased in all brain structures. The organoselenium also inhibited CK activity in the cerebral cortex. Therefore, changes in motor behaviour, redox state and energy homeostasis in rats treated acutely with organoselenium support the hypotheses that the brain is a potential target for the organochalcogen action. Ltd.
Assuntos
Encéfalo/metabolismo , Compostos Organosselênicos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Animais , Encéfalo/enzimologia , Catalase/metabolismo , Creatina Quinase/metabolismo , Masculino , Compostos Organosselênicos/química , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismoRESUMO
The organoselenium compound, dicholesteroyl diselenide (DCDS) is a structural analogue of diphenyl diselenide (DPDS) and may be considered as a promising antioxidant drug in vivo. Nevertheless, little is known about the toxicological properties of DCDS. In the present study we evaluated the cytotoxic, genotoxic and mutagenic properties of DCDS in Chinese hamster lung fibroblasts (V79) and in strains of the yeast Saccharomyces cerevisiae, proficient and deficient in several DNA-repair pathways. The results with V79 cells show that DCDS induced cytotoxicity, GSH depletion and elevation of lipid peroxidation at lower concentrations than did DPDS. DCDS also generated single- and double-strand DNA breaks in V79 cells, both in the presence and in the absence of metabolic activation, as revealed by alkaline and neutral comet assays. Moreover, the induction of oxidative DNA base-damage was demonstrated by means of a modified comet assay with formamidopyrimidine-DNA glycosylase and endonuclease III. Treatment with DCDS also induced micronucleus formation in V79 cells as well as point and frame-shift mutations in a haploid wild-type strain of S. cerevisiae. Yeast mutants defective in base excision-repair proteins were the most sensitive to DCDS. Pre-incubation with N-acetylcysteine reduced DCDS's oxidative, genotoxic and mutagenic effects in yeast and in V79 cells. Our findings indicate that the presence of cholesteroyl substituents in DCDS results in elevation of its cytotoxic and genotoxic potential compared with that of DPDS in yeast and in V79 cells. However, due to dose-dependent contrasting behaviour of organoselenium compounds and differences in their toxicity in in vitro and in vivo systems, further studies are needed in order to establish the non-toxic concentration range for treatment in mammals.
Assuntos
Colesterol/análogos & derivados , Dano ao DNA , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Mutagênicos/toxicidade , Compostos Organosselênicos/toxicidade , Saccharomyces cerevisiae/efeitos dos fármacos , Animais , Biomarcadores/análise , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Colesterol/toxicidade , Ensaio Cometa , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Mutação da Fase de Leitura/efeitos dos fármacos , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Testes para Micronúcleos , Estresse Oxidativo/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Testes de Toxicidade/métodosRESUMO
The present study evaluated the antinociceptive and anti-inflammatory effects of per oral (p.o.) administration of salicylic acid-derivative organoselenium compounds in chemical models of nociception in mice. The compounds (50 mg/kg; p.o.) were administered 30 and 60 min before the nociceptive behavior and compared to the positive-control, acetylsalicylic acid (ASA; 200 mg/kg; p.o.). In addition, a dose-response curve (25-100 mg/kg) for compounds was carried out in the formalin test. When assessed in the chemical models, acetic acid-induced writhing behavior, formalin and glutamate tests, the compounds showed the following antinociceptive profile 1B>2B>1A>2A, suggesting a chemical structure-dependent relationship. Then, the anti-inflammatory properties and toxicological potential of compound 1B were investigated. Compound 1B, similar to the positive-control, ASA, diminished the edema formation and decreased the myeloperoxidase activity induced by croton oil (2.5%) in the ear tissue. The results also indicate that a single oral administration of 1B caused neither signs of acute toxicity nor those of gastrointestinal injury. The administration of 1B did not alter the water and food intakes, plasma alanine and aspartate aminotransferase activities or urea levels and cerebral or hepatic δ-aminolevulinate dehydratase activity. Salicylic acid-derivative organoseleniums, mainly compound 1B, have been found to be novel compounds with antinociceptive/anti-inflammatory properties; nevertheless, more studies are required to examine their therapeutic potential for pain treatment.
Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Compostos Organosselênicos/farmacologia , Salicilatos/farmacologia , Administração Oral , Animais , Aspirina/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Fígado/efeitos dos fármacos , Masculino , Camundongos , Compostos Organosselênicos/administração & dosagem , Compostos Organosselênicos/toxicidade , Medição da Dor , Peroxidase/metabolismo , Espécies Reativas de Nitrogênio/metabolismo , Salicilatos/administração & dosagem , Salicilatos/toxicidadeRESUMO
Studies of our group has demonstrated that (PhSe)2 plays some pharmacologic activities. In addition, it is possible that this compound would be an alternative source of organic selenium in animal foods. However, previous works showed that diphenyl diselenide (PhSe)2 and diphenyl ditelluride (PhTe)2 are toxic for mammals, but their undesirable effects were never tested in avian models. Then, the present study was carried to examine the possible teratogenic effects of (PhSe)2 and (PhTe)2 on chicken embryo development. The eggs were injected with (PhSe)2 at 0, 1 and 10 nmol or with (PhTe)2 at 4 nmol. The control was injected with 10 µl of soya bean oil (vehicle). In order to determine the possible toxic effect of these chemicals, we measure the embryo dimensions, the encephalon, heart and liver weight, thiobarturic acid reactive species (TBARS) level and the δ-aminonevulinate dehydratase (ALA-D) activity. (PhSe)2 and (PhTe)2 did not affect the embryo dimensions. Treatment with (PhSe)2 at 10 nmol per egg caused a increase on TBARS level and on ALA-D activity of the liver tissue, whereas (PhTe)2 decreased encephalon weight, had a tendency to increase to increase TBARS level but did not affect ALA-D activity. Taken together, these results indicate that (PhSe)2 and (PhTe)2 are slightly toxic for chicken embryos. Furthermore, (PhTe)2 caused a decrease in encephalon, which indicates its neurotoxicity. Finally, these results indicate that (PhTe)2 seems not be promissory for therapeutic applications, whereas (PhSe)2 could be of clinical and/or nutritional concern, which will be target for further researches.
Assuntos
Derivados de Benzeno/toxicidade , Desenvolvimento Embrionário/efeitos dos fármacos , Compostos Organometálicos/toxicidade , Compostos Organosselênicos/toxicidade , Teratogênicos/toxicidade , Ácido Aminolevulínico/metabolismo , Animais , Derivados de Benzeno/química , Encéfalo/efeitos dos fármacos , Encéfalo/embriologia , Encéfalo/metabolismo , Embrião de Galinha , Relação Dose-Resposta a Droga , Coração/efeitos dos fármacos , Coração/embriologia , Fígado/efeitos dos fármacos , Fígado/embriologia , Fígado/metabolismo , Estrutura Molecular , Tamanho do Órgão/efeitos dos fármacos , Compostos Organometálicos/química , Compostos Organosselênicos/química , Teratogênicos/química , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
AIMS: The study investigated the antidepressant-like effect and acute toxicity of 4-phenyl-1-(phenylselanylmethyl)-1,2,3-triazole (Se-TZ), an organoselenium-containing heterocycle compound in mice. MAIN METHODS: The antidepressant-like effect of Se-TZ (1-50mg/kg) and its mechanism of action, was analyzed in the tail suspension test (TST) in male C57BL/6J mice. Additionally, the levels of the monoamines and their metabolites in cerebral cortex and hippocampus were analyzed by high-performance liquid chromatography. To investigate the potential acute toxicity caused by Se-TZ, the mice received a single oral dose of Se-TZ (1-50mg/kg), and after 72h were performed the assays. KEY FINDINGS: The Se-TZ (5-50mg/kg) significantly reduced immobility time in TST without altering locomotor and exploratory activities. The antidepressant-like effect of Se-TZ (25mg/kg) in the TST was prevented by pre-treatment of mice with SCH23390, sulpiride and methysergide, but not with prazosin, yohimbine and propranolol. Se-TZ, increased monoamine neurotransmitters dopamine and serotonin levels in the cerebral cortex and hippocampus, whereas norepinephrine turnover was not changed. This study also demonstrated that the Se-TZ, did not cause the acute toxicity in biochemical markers hepatic and renal investigated. The results evidenced that exposure to Se-TZ caused a significant increase in the catalase (CAT) activity in the cerebral cortex and hippocampus, however the glutathione S-transferase (GST) activity increased only in the cerebral cortex. SIGNIFICANCE: These results suggest that Se-TZ demonstrated antidepressant-like effect, mediated via the central dopaminergic and serotoninergic neurotransmitter systems which may be of interest as a therapeutic agent for the treatment of depressive disorders.
Assuntos
Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Dopamina/metabolismo , Compostos Organosselênicos/farmacologia , Serotonina/metabolismo , Triazóis/farmacologia , Animais , Antidepressivos/administração & dosagem , Antidepressivos/toxicidade , Catalase/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Glutationa Transferase/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Norepinefrina/metabolismo , Compostos Organosselênicos/administração & dosagem , Compostos Organosselênicos/toxicidade , Fatores de Tempo , Testes de Toxicidade Aguda , Triazóis/administração & dosagem , Triazóis/toxicidadeRESUMO
Diphenyl diselenide (DPDS) is an electrophilic reagent used in the synthesis of a variety of pharmacologically active organoselenium compounds. Studies have shown its interesting pharmacodinamic properties, as antioxidant, antimutagenic and antitumoral effects. Here we report the antigenotoxic properties of DPDS against tamoxifen (TAM)-induced oxidative DNA damage in MCF-7 cultured cell line. We determined the cytotoxicity by lactate dehydrogenase (LDH) leakage assay and evaluated oxidative DNA damage by modified comet assay employing the enzymes formamidopyrimidine DNA-glycosylase (Fpg) and endonuclease III (Endo III). Our results demonstrate that the cellular effects of DPDS appear to be complex and concentration-dependent. The present findings show that DPDS is not genotoxic (at concentrations lower than 2.0µmol/L) in MCF-7 cells, as observed in the modified comet assay. Moreover, DPDS protects against TAM-induced oxidative DNA damage, probably by its antioxidant activity, without interfering with its cytotoxicity. In this manner, the treatment with low concentrations of DPDS, a synthetic organoselenium compound, could be used as a potent antigenotoxic agent to prevent the risk of cancer induction triggered by tamoxifen hormone therapy. Thereby, more studies concerning the toxicity of DPDS and its structural derivatives are still necessary for future safe therapeutic application and development of novel chemopreventive compounds for combined therapy in breast cancer.
Assuntos
Antimutagênicos/farmacologia , Antineoplásicos Hormonais/toxicidade , Derivados de Benzeno/farmacologia , Compostos Organosselênicos/farmacologia , Tamoxifeno/toxicidade , Antimutagênicos/administração & dosagem , Antimutagênicos/toxicidade , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Antioxidantes/toxicidade , Derivados de Benzeno/administração & dosagem , Derivados de Benzeno/toxicidade , Neoplasias da Mama/patologia , Ensaio Cometa , Dano ao DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Células MCF-7 , Compostos Organosselênicos/administração & dosagem , Compostos Organosselênicos/toxicidade , Estresse Oxidativo/efeitos dos fármacosRESUMO
Organochalcogens, such as organoselenium and organotellurium compounds, can be neurotoxic to rodents. Since mitochondrial dysfunction plays a pivotal role in neurological disorders, the present study was designed to test the hypothesis that rat brain mitochondrial complexes (I, II, I-III, II-III and IV) could be molecular targets of organochalcogens. The results show that organochalcogens caused statistically significant inhibition of mitochondrial complex I activity, which was prevented by preincubation with NADH and fully blunted by reduced glutathione (GSH). Mitochondrial complex II activity remained unchanged in response to (PhSe)2 treatment. Ebs and (PhTe)2 caused a significant concentration-dependent inhibition of complex II that was also blunted by GSH. Mitochondrial complex IV activity was not modified by organochalcogens. Collectively, Ebs, (PhSe)2 and (PhTe)2 were more effective inhibitors of brain mitochondrial complex I than of complex II, whereas they did not affect complex IV. These observations are consistent with organochalcogens inducing mitochondrial complex I and II inhibition via their thiol-oxidase-like activity, with Ebs, (PhSe)2 and (PhTe)2 effectively oxidising critical thiol groups of these complexes.