RESUMO
Alzheimer's disease (AD) is a multifactorial pathology characterized by amyloid deposits, neurofibrillary formation, oxidative stress and cholinergic system dysfunction. In this sense, here we report the rational design of a multi-target directed ligand (MTDL) for AD based on virtual screening and bioinformatic analyses, exploring the molecular targets ß-secretase (BACE-1), glycogen synthase kinase-3ß (GSK-3ß) and acetylcholinesterase (AChE). After this screening, the compound with higher molecular docking affinity was selected, the 1-(7-chloroquinolin-4-yl)-N-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazole-4 carboxamide(QTC-4-MeOBnE). To further our studies, the protective effect of QTC-4-MeOBnE (0.1 and 1 mg/kg for 20 days) on STZ-induced sporadic AD mice was determined. QTC-4-MeOBnE pretreatment attenuated cognitive and memory deficit induced by STZ in an object recognition test, Y-maze, social recognition test and step-down passive avoidance. The mechanisms underlying this action might be attributed to the reduction of lipid peroxidation and reactive species formation in the prefrontal cortex and hippocampus of mice submitted to STZ. In addition, QTC-4-MeOBnE pretreatment abolished the up-regulation of AChE activity and the overexpression of GSK 3ß and genes involved in amyloid cascade such as BACE-1, protein precursor amyloid, Ñ-secretase, induced by STZ. Moreover, toxicological parameters were not modified by QTC-4-MeOBnE chronic treatment. This evidence suggests that QTC-4-MeOBnE exerts its therapeutic effect through multiple pathways involved in AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Cognição/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Quinolinas/uso terapêutico , Triazóis/uso terapêutico , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/patologia , Animais , Modelos Animais de Doenças , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Camundongos , Simulação de Acoplamento Molecular , EstreptozocinaRESUMO
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
Organic selenium and tellurium compounds are known for their broad-spectrum effects in a variety of experimental disease models. However, these compounds commonly display high toxicity and the molecular mechanisms underlying these deleterious effects have yet to be elucidated. Thus, the need for an animal model that is inexpensive, amenable to high-throughput analyses, and feasible for molecular studies is highly desirable to improve organochalcogen pharmacological and toxicological characterization. Herein, we use Caenorhabdtis elegans (C. elegans) as a model for the assessment of pharmacological and toxicological parameters following exposure to two 4-phenylchalcogenil-7-chloroquinolines derivatives (PSQ for selenium and PTQ for tellurium-containing compounds). While non-lethal concentrations (NLC) of PTQ and PSQ attenuated paraquat-induced effects on survival, lifespan and oxidative stress parameters, lethal concentrations (LC) of PTQ and PSQ alone are able to impair these parameters in C. elegans. We also demonstrate that DAF-16/FOXO and SKN-1/Nrf2 transcription factors underlie the mechanism of action of these compounds, as their targets sod-3, gst-4 and gcs-1 were modulated following exposures in a daf-16- and skn-1-dependent manner. Finally, in accordance with a disturbed thiol metabolism in both LC and NLC, we found higher sensitivity of trxr-1 worm mutants (lacking the selenoprotein thioredoxin reductase 1) when exposed to PSQ. Finally, our study suggests new targets for the investigation of organochalcogen pharmacological effects, reinforcing the use of C. elegans as a powerful platform for preclinical approaches.
Assuntos
Antioxidantes/farmacologia , Caenorhabditis elegans/efeitos dos fármacos , Calcogênios/farmacologia , Compostos Organometálicos/farmacologia , Compostos Organosselênicos/farmacologia , Quinolinas/farmacologia , Telúrio/farmacologia , Animais , Antioxidantes/síntese química , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Calcogênios/síntese química , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Longevidade/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Compostos Organometálicos/síntese química , Compostos Organosselênicos/síntese química , Oxidantes/antagonistas & inibidores , Oxidantes/toxicidade , Estresse Oxidativo , Paraquat/antagonistas & inibidores , Paraquat/toxicidade , Quinolinas/síntese química , Transdução de Sinais , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Breast cancer is a major public health burden in both developed and developing countries and there is still a need to screen new molecules with different modes of actions. The aims of this study were to evaluate the selectivity profile, apoptotic cell death and cell cycle arrest induced by 7-chloroquinoline-1,2,3-triazoyl carboxamides derivatives in hormonal-dependent and hormonal-independent breast cancer cells. Results showed significantly decreased MCF-7 and MDA-MB-231 cells viability in vitro in a dose dependent manner after treatment with 7-chloroquinoline derivatives QTCA-1, QTCA-2 and QTCA-3. QTCA-1 displayed the highest cytotoxic activity from all the tested compounds in MDA-MB-231 with IC50 values of 20.60, 20.42 and 19.91µM in 24, 48 and 72h of treatment respectively. Apoptosis induction was also significantly higher in the hormonal-independent breast cancer cells, with 80.4% of dead cells in MDA-MB-231 and only 16.8% of dead in MCF-7 cells. As a result, G0/G1 cycle arrest was observed in MCF-7 cells and no cell cycle arrest at all was observed in MDA-MB-231 cells. Molecular docking showed a high affinity of QTCA-1 to PARP-1, Scr and PI3K/mTOR targets. These results suggest a strong activity of the 7-chloroquinoline derivative QTCA-1 in independent-hormonal cells and suggest selectivity for triple negative cells.
Assuntos
Apoptose/efeitos dos fármacos , Triazóis/farmacologia , Neoplasias de Mama Triplo Negativas/patologia , Feminino , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Triazóis/químicaRESUMO
We described herein our results on the silver-catalyzed synthesis of diaryl selenides via a cross-coupling reaction of diaryl diselenides with aryl boronic acids. The methodology is tolerant to electron-donor and electron-withdrawing groups at the substrates and the desired products were obtained in good to excellent yields.
RESUMO
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.