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1.
Cell Physiol Biochem ; 54(1): 126-141, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32017483

RESUMO

BACKGROUND/AIMS: Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter and hormone with important physiological functions in many organs, including the intestine. We have previously shown that 5-HT activates the aryl hydrocarbon receptor (AhR) in intestinal epithelial cells (IECs) via a serotonin transporter (SERT)-dependent mechanism. AhR is a nuclear receptor that binds a variety of molecules including tryptophan (TRP) metabolites to regulate physiological processes in the intestine including xenobiotic detoxification and immune modulation. We hypothesized that 5-HT activates AhR indirectly by interfering with metabolic clearance of AhR ligands by cytochrome P450 1A1 (CYP1A1). METHODS: Inhibition of CYP1A1 activity by 5-HT was assessed in the human intestinal epithelial cell line Caco-2 and recombinant CYP1A1 microsomes using both luciferase and LC-MS/MS. Degradation of 5-HT by recombinant CYP1A1 was measured by LC-MS/MS. For in vitro studies, CYP1A1 and CYP1B1 mRNA expression levels were measured by RT-PCR and CYP1A1 activity was measured by ethoxyresorufin-O-deethylase (EROD) assays. For in vivo studies, AhR ligands were administered to SERT KO mice and WT littermates and intestinal mucosa CYP1A1 mRNA was measured. RESULTS: We show that 5-HT inhibits metabolism of both the pro-luciferin CYP1A1 substrate Luc-CEE as well as the high affinity AhR ligand 6-formylindolo[3,2-b] carbazole (FICZ). Recombinant CYP1A1 assays revealed that 5-HT is metabolized by CYP1A1 in an NADPH dependent manner. Treatment with 5-HT in TRP-free medium, which is devoid of trace AhR ligands, showed that 5-HT requires the presence of AhR ligands to activate AhR. Cotreatment with 5-HT and FICZ confirmed that 5-HT potentiates induction of AhR target genes by AhR ligands. However, this was only true for ligands which are CYP1A1 substrates such as FICZ. Administration of ß-napthoflavone by gavage or indole-3-carbinol via diet to SERT KO mice revealed that lack of SERT impairs intestinal AhR activation. CONCLUSION: Our studies provide novel evidence of crosstalk between serotonergic and AhR signaling where 5-HT can influence the ability of AhR ligands to activate the receptor in the intestine.


Assuntos
Citocromo P-450 CYP1A1/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Serotonina/farmacologia , Transcrição Genética/efeitos dos fármacos , Animais , Células CACO-2 , Carbazóis/farmacologia , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP1B1/metabolismo , Humanos , Ligantes , Masculino , Camundongos , Camundongos Knockout , RNA Mensageiro/metabolismo , Receptores de Hidrocarboneto Arílico/química , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/deficiência , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Transdução de Sinais/efeitos dos fármacos , Especificidade por Substrato , beta-Naftoflavona/administração & dosagem
2.
Gut ; 69(2): 329-342, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31439637

RESUMO

OBJECTIVE: Facilitates Chromatin Transcription (FACT) complex is a histone chaperone participating in DNA repair-related and transcription-related chromatin dynamics. In this study, we investigated its oncogenic functions, underlying mechanisms and therapeutic implications in human hepatocellular carcinoma (HCC). DESIGN: We obtained HCC and its corresponding non-tumorous liver samples from 16 patients and identified FACT complex as the most upregulated histone chaperone by RNA-Seq. We further used CRISPR-based gene activation and knockout systems to demonstrate the functions of FACT complex in HCC growth and metastasis. Functional roles and mechanistic insights of FACT complex in oxidative stress response were investigated by ChIP assay, flow cytometry, gene expression assays and 4sU-DRB transcription elongation assay. Therapeutic effect of FACT complex inhibitor, Curaxin, was tested in both in vitro and in vivo models. RESULTS: We showed that FACT complex was remarkably upregulated in HCC and contributed to HCC progression. Importantly, we unprecedentedly revealed an indispensable role of FACT complex in NRF2-driven oxidative stress response. Oxidative stress prevented NRF2 and FACT complex from KEAP1-mediated protein ubiquitination and degradation. Stabilised NRF2 and FACT complex form a positive feedback loop; NRF2 transcriptionally activates the FACT complex, while FACT complex promotes the transcription elongation of NRF2 and its downstream antioxidant genes through facilitating rapid nucleosome disassembly for the passage of RNA polymerase. Therapeutically, Curaxin effectively suppressed HCC growth and sensitised HCC cell to sorafenib. CONCLUSION: In conclusion, our findings demonstrated that FACT complex is essential for the expeditious HCC oxidative stress response and is a potential therapeutic target for HCC treatment.


Assuntos
Carcinoma Hepatocelular/fisiopatologia , Proteínas de Ligação a DNA/fisiologia , Proteínas de Grupo de Alta Mobilidade/fisiologia , Chaperonas de Histonas/fisiologia , Neoplasias Hepáticas/fisiopatologia , Estresse Oxidativo/fisiologia , Fatores de Elongação da Transcrição/fisiologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carbazóis/farmacologia , Carbazóis/uso terapêutico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/prevenção & controle , Proteínas de Ciclo Celular/deficiência , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/genética , Movimento Celular/fisiologia , Proliferação de Células/genética , Proliferação de Células/fisiologia , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/fisiologia , Técnicas de Inativação de Genes/métodos , Proteínas de Grupo de Alta Mobilidade/antagonistas & inibidores , Proteínas de Grupo de Alta Mobilidade/biossíntese , Proteínas de Grupo de Alta Mobilidade/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas Experimentais/genética , Neoplasias Hepáticas Experimentais/patologia , Neoplasias Hepáticas Experimentais/fisiopatologia , Neoplasias Hepáticas Experimentais/prevenção & controle , Camundongos Endogâmicos BALB C , Camundongos Nus , Estresse Oxidativo/genética , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Fatores de Transcrição/fisiologia , Fatores de Elongação da Transcrição/antagonistas & inibidores , Fatores de Elongação da Transcrição/biossíntese , Fatores de Elongação da Transcrição/genética , Regulação para Cima/fisiologia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Am J Vet Res ; 80(11): 1001-1006, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31644340

RESUMO

OBJECTIVE: To investigate the ability of a proprietary antagonist of E-type prostanoid receptor (EP) 4, grapiprant, and carprofen to attenuate lameness attributable to urate-induced synovitis in dogs. ANIMALS: 5 purpose-bred hound-cross dogs. PROCEDURES: A blinded, 3-way crossover study was performed. Dogs received each of 3 treatments (L-766, a proprietary antagonist of EP4; 4.0 mg/kg), grapiprant (an antagonist of EP4; 2.0 mg/kg), and carprofen (4.4 mg/kg); dogs received 4 doses of each treatment (14 and 2 hours before and 22 and 46 hours after urate injection). Synovitis was induced by intra-articular injection of sodium urate. Measurements (vertical ground reaction forces and clinical lameness scores) were obtained immediately before (0 hours; baseline) and 6, 12, 24, 36, and 48 hours after sodium urate injection. All data were analyzed with repeated-measures ANOVA. RESULTS: Lameness scores at 6 hours were significantly higher than baseline lameness scores for all treatments. Lameness scores for the grapiprant treatment remained significantly higher at 12 and 24 hours, compared with baseline lameness scores. Lameness scores for the carprofen treatment were significantly lower than lameness scores for the grapiprant treatment at 6, 12, and 24 hours. Analysis of peak vertical force and vertical impulse data revealed a pattern similar to that for lameness scores. Treatment with L-766 resulted in a significantly higher vertical impulse at 48 hours than did treatment with carprofen or grapiprant. CONCLUSIONS AND CLINICAL RELEVANCE: In these dogs, carprofen was the most effective treatment for attenuating lameness induced by injection of sodium urate, and grapiprant was the least effective treatment.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Carbazóis/uso terapêutico , Doenças do Cão/tratamento farmacológico , Coxeadura Animal/tratamento farmacológico , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Compostos de Sulfonilureia/uso terapêutico , Sinovite/veterinária , Animais , Carbazóis/farmacologia , Estudos Cross-Over , Cães , Marcha , Injeções Intra-Articulares/veterinária , Coxeadura Animal/induzido quimicamente , Masculino , Método Simples-Cego , Sinovite/induzido quimicamente , Sinovite/tratamento farmacológico , Ácido Úrico
4.
Eur J Med Chem ; 183: 111741, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31605873

RESUMO

Tumor-associated macrophages (TAMs) are one of the prominent components of the tumor microenvironment (TME). The polarization peculiarity of TAMs drives them to infiltrate and active with states between M1 (anti-tumor) and M2 (pro-tumor) phenotypes in cancers. Exploiting small molecular drugs through targeting TAMs to repolarize them into an antitumor phenotype is considered as a novel strategy for cancer treatments in recent years. For discovering novel compounds that target TAMs, a series of ureido tetrahydrocarbazole derivatives were designed, synthesized and evaluated both in vitro and in vivo. Among them, compound 23a was found to dose-dependently repolarize TAMs from M2 to M1 both in vitro and in vivo. And more importantly, the in vivo experiments also revealed that compound 23a was capable of remarkably inhibiting tumor growth of the LLC mouse model. Moreover, the synergy of compound 23a with anti-PD-1 antibody had more superior antineoplastic effects than the exclusive use of either in vivo.


Assuntos
Antineoplásicos/síntese química , Carbazóis/síntese química , Macrófagos/efeitos dos fármacos , Ureia/análogos & derivados , Ureia/síntese química , Animais , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Carbazóis/administração & dosagem , Carbazóis/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Descoberta de Drogas/métodos , Sinergismo Farmacológico , Feminino , Humanos , Macrófagos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7 , Relação Estrutura-Atividade , Microambiente Tumoral , Ureia/administração & dosagem , Ureia/farmacologia
5.
Kyobu Geka ; 72(11): 889-892, 2019 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-31588102

RESUMO

Few cases of lung mucoepidermoid carcinomas with anaplastic lymphoma kinase (ALK) fusion have been reported. A 35-year-old woman was found to have an abnormal chest X-ray. A tumor and obstructive pneumonitis in her left upper lobe was detected using computed tomography (CT). She was admitted to our hospital, and was diagnosed with mucoepidermoid carcinoma by transbronchial biopsy. Left pneumonectomy and lymphadenectomy were performed for lung mucoepidermoid carcinoma and a mediastinal lymph node metastasis (pT2aN2M0, stage ⅢA). Postoperative radiotherapy (50 Gy) to the mediastinum and chemotherapy were performed followed by several radiotherapies for cervical and mediastinal lymph node and right ischium metastases. Since then, further radiotherapy was impossible. However, we detected ALK fusion in the resected specimen and the cancer responded to alectinib hydrochloride.


Assuntos
Carcinoma Mucoepidermoide , Neoplasias Pulmonares , Adulto , Quinase do Linfoma Anaplásico , Carbazóis , Feminino , Humanos , Excisão de Linfonodo , Piperidinas
6.
Adv Mater ; 31(44): e1904799, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31523871

RESUMO

Nonlinear optical microscopy has become a powerful tool in bioimaging research due to its unique capabilities of deep optical sectioning, high-spatial-resolution imaging, and 3D reconstruction of biological specimens. Developing organic fluorescent probes with strong nonlinear optical effects, in particular third-harmonic generation (THG), is promising for exploiting nonlinear microscopic imaging for biomedical applications. Herein, a simple method for preparing organic nanocrystals based on an aggregation-induced emission (AIE) luminogen (DCCN) with bright near-infrared emission is successfully demonstrated. Aggregation-induced nonlinear optical effects, including two-photon fluorescence (2PF), three-photon fluorescence (3PF), and THG, of DCCN are observed in nanoparticles, especially for crystalline nanoparticles. The nanocrystals of DCCN are successfully applied for 2PF microscopy at 1040 nm NIR-II excitation and THG microscopy at 1560 nm NIR-II excitation, respectively, to reconstruct the 3D vasculature of the mouse cerebral vasculature. Impressively, the THG microscopy provides much higher spatial resolution and brightness than the 2PF microscopy and can visualize small vessels with diameters of ≈2.7 µm at the deepest depth of 800 µm in a mouse brain. Thus, this is expected to inspire new insights into the development of advanced AIE materials with multiple nonlinearity, in particular THG, for multimodal nonlinear optical microscopy.


Assuntos
Vasos Sanguíneos/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Corantes Fluorescentes/química , Microscopia de Fluorescência por Excitação Multifotônica/métodos , Pontos Quânticos/química , Animais , Benzopiranos/química , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Carbazóis/química , Teoria da Densidade Funcional , Feminino , Humanos , Camundongos Endogâmicos ICR , Nanopartículas , Nitrilos/química , Espectroscopia de Luz Próxima ao Infravermelho
7.
Ecotoxicol Environ Saf ; 184: 109609, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31518828

RESUMO

Carbazole and halogenated carbazoles have been widely detected throughout the environment in soil, river deposits, and lake sediments. Human exposure to these compounds may occur through inhalation, drinking water, dietary intake and/or skin contact, and exposure levels in the body may be evaluated by measuring them in serum or blood. This paper reports the method development and validation for the analysis of carbazole and 11 halogenated carbazoles in human blood and/or serum samples. A small sample size of 100 µL of blood or serum was employed for the analysis. The samples were prepared through salting-out liquid-liquid extraction (LLE) by using hexane/ethyl acetate (4:1, v/v) as the extraction solvent and aqueous MgSO4 (37.5 wt%) as the salting-out regent, respectively. Sample analysis was performed using gas-chromatography (GC) coupled with a tandem mass spectrometer (MS/MS) in an electron impact (EI) mode. The developed method demonstrated low detection limits in the range of 0.02-0.27 ng/mL, intra-day accuracy ranging from 81.2% to 125%, and inter-day accuracy from 91.0% to 117%. The intra- and inter-day precisions, calculated by relative standard deviations (RSDs), were in the ranges of 1.0-16.0% and 1.8-16.4%, respectively. The developed method was applied to the analysis of 50 human serum samples collected from pregnant women in Southern California in 2012. Low concentrations of carbazole were measured in 18 samples, while halogenated carbazoles were not detected in any of the samples.


Assuntos
Análise Química do Sangue/métodos , Carbazóis/sangue , Exposição Ambiental/análise , Cromatografia Gasosa-Espectrometria de Massas , Espectrometria de Massas em Tandem , California , Feminino , Halogenação , Humanos , Limite de Detecção , Gravidez
8.
J Enzyme Inhib Med Chem ; 34(1): 1544-1561, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31448648

RESUMO

In this paper, a series of novel 1H-dibenzo[a,c]carbazole derivatives of dehydroabietic acid bearing different N-(piperazin-1-yl)alkyl side chains were designed, synthesised and evaluated for their in vitro anticancer activities against three human hepatocarcinoma cell lines (SMMC-7721, HepG2 and Hep3B). Among them, compound 10g exhibited the most potent activity against three cancer cell lines with IC50 values of 1.39 ± 0.13, 0.51 ± 0.09 and 0.73 ± 0.08 µM, respectively. In the kinase inhibition assay, compound 10g could significantly inhibit MEK1 kinase activity with IC50 of 0.11 ± 0.02 µM, which was confirmed by western blot analysis and molecular docking study. In addition, compound 10g could elevate the intracellular ROS levels, decrease mitochondrial membrane potential, destroy the cell membrane integrity, and finally lead to the oncosis and apoptosis of HepG2 cells. Therefore, compound 10g could be a potent MEK inhibitor and a promising anticancer agent worthy of further investigations.


Assuntos
/farmacologia , Antineoplásicos/farmacologia , Carbazóis/farmacologia , MAP Quinase Quinase 1/antagonistas & inibidores , Piperazina/farmacologia , Inibidores de Proteínas Quinases/farmacologia , /síntese química , Antineoplásicos/síntese química , Antineoplásicos/química , Carbazóis/síntese química , Carbazóis/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , MAP Quinase Quinase 1/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Piperazina/síntese química , Piperazina/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
9.
Eur J Med Chem ; 182: 111571, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31425908

RESUMO

Anaplastic lymphoma kinase (ALK), an oncogenic receptor tyrosine kinase, is a therapeutic target in various cancers, including non-small cell lung cancer. Although several ALK inhibitors, including crizotinib, ceritinib, and alectinib, are approved for cancer treatment, their long-term benefit is often limited by the cancer's acquisition of resistance owing to secondary point mutations in ALK. Importantly, some ALK inhibitors cannot cross the blood-brain barrier (BBB) and thus have little or no efficacy against brain metastases. The introduction of a lipophilic moiety, such as a fluoroethyl group may improve the drug's BBB penetration. Herein, we report the synthesis of fluoroethyl analogues of crizotinib 1, alectinib 4, and ceritinib 9, and their radiolabeling with 18F for pharmacokinetic studies. The fluoroethyl derivatives and their radioactive analogues were obtained in good yields with high purity and good molar activity. A cytotoxicity screen in ALK-expressing H2228 lung cancer cells showed that the analogues had up to nanomolar potency and the addition of the fluorinated moiety had minimal impact overall on the potency of the original drugs. Positron emission tomography in healthy mice showed that the analogues had enhanced BBB penetration, suggesting that they have therapeutic potential against central nervous system metastases.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/farmacologia , Carbazóis/farmacologia , Crizotinibe/farmacologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Sulfonas/farmacologia , Quinase do Linfoma Anaplásico/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Carbazóis/síntese química , Carbazóis/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Crizotinibe/síntese química , Crizotinibe/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Radioisótopos de Flúor , Humanos , Camundongos , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Tomografia por Emissão de Pósitrons , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Cintilografia , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/química , Distribuição Tecidual
10.
Mar Pollut Bull ; 146: 393-398, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31426173

RESUMO

A suite of eight polyhalogenated carbazole (PHCZ) congeners were detected in sediments of the Jiaozhou Bay wetland. 3,6-dichlorocarbazole (36-CCZ), and 3,6-dibromocarbazole (36-BCZ) were detected in all samples. The concentrations of ΣPHCZs ranged from 6.9 to 33.4 ng/g dry weight (dw). The recovery of surrogate standard ranged from 85 to 109%. Significant relationships were found between the concentrations of 36-CCZ and those of the other three detected compounds (36-BCZ, 36-ICZ, and 1368-BCZ). However, with regard to the other chemicals, only 1368-BCZ was related to 36-ICZ. The toxic equivalent (TEQ) was used to assess the relative toxicity of PHCZs, which ranged within 0.1-3.9 pg TEQ/g dw in sediment. The inventory of ΣPHCZs was 58.9 kg. These results indicate that PHCZs are widely distributed in the Jiaozhou wetland and the dyeing and finishing industries may be important contamination sources of PHCZs.


Assuntos
Carbazóis/análise , Carbazóis/toxicidade , Sedimentos Geológicos/análise , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade , Baías/análise , Carbazóis/química , China , Ecotoxicologia/métodos , Monitoramento Ambiental/métodos , Áreas Alagadas
11.
Mar Pollut Bull ; 146: 718-728, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31426214

RESUMO

The sorption of 5 Polyhalogenated carbazoles (PHCs) [3,6-dibromocarbazole (3,6-BCZ), 3,6-dichlorocarbazole (3,6-CCZ), 3,6-diiodocarbazole (3,6-ICZ), 2,7-dibromocarbazole (2,7-BCZ) and 3-bromocarbazole (3-BCZ)] on to three microplastics [polyethylene (PE), polypropylene (PP), and polyvinyl chloride (PVC)] in a simulated seawater system are studied. Sorption isotherms demonstrated that PVC had the maximum sorption capacity, which can be attributed to polar-polar interaction. The sorption kinetics model showed that the sorption process was controlled by both intraparticle and film diffusion. The sorption of PHCs to microplastics was significantly influenced by temperature, the sorption capacity first increased gradually and then decreased with the increasing temperature. Increasing the salinity decreased the sorption of PHCs onto PP, PE, PVC microplastics. Our results indicated that all three kinds of microplastics can serve as carriers for PHCs in the aquatic environment, which put marine ecosystems at higher risks.


Assuntos
Carbazóis/química , Plásticos/química , Água do Mar/química , Poluentes Químicos da Água/química , Adsorção , Difusão , Cinética , Salinidade , Temperatura Ambiente
12.
Ecotoxicol Environ Saf ; 182: 109470, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31352212

RESUMO

In the past few years, polyhalogenated carbazoles (PHCZs) have been of increasing concern because their structure is similar to that of legacy POPs. In the present study, an analytical method, including intensive cleanup and fractionation procedures in combination with instrumental parameters, was developed to determine ultratrace polyhalogenated carbazoles (PHCZs) in soil and sediment. The eluting sorbents, volume and packing of the column were optimized. Our results showed that 5 g of florisil and 4 g of silica gel under 150 mL of hexane/DCM = 3:1 presented good performance in terms of recovery and repeatability. GC-HRMS, GC-MS/MS (EI-MRM) and GC-MS (EI-SIM) were applied to compare the performance of PHCZ analysis. For sensitivity, EI-MRM presents method detection limits comparable to those of GC-HRMS and much lower than those of EI-SIM. Regarding selectivity, GC-HRMS performed better than the other two techniques since GC-HRMS can reduce interference from perfluorokerosene (PFK) and DDX (DDT, DDE, and DDD) due to its high resolution. GC-HRMS was then further optimized by shortening the run time and modifying the SIM ion. The final method was successfully applied to determine PHCZs in soil and sediment, and the target compounds had almost 100% detection frequency in the samples. The ubiquitous presence of PHCZ in soil and sediment calls for a further investigation of its source, distribution and degradation in the environment.


Assuntos
Carbazóis/análise , Recuperação e Remediação Ambiental/métodos , Sedimentos Geológicos/química , Hidrocarbonetos Halogenados/análise , Poluentes do Solo/análise , Solo/química , Cromatografia Gasosa-Espectrometria de Massas , Hexanos/química , Limite de Detecção , Silicatos de Magnésio/química , Dióxido de Silício/química , Espectrometria de Massas em Tandem
13.
J Enzyme Inhib Med Chem ; 34(1): 1321-1346, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31328585

RESUMO

For over half a century, the carbazole skeleton has been the key structural motif of many biologically active compounds including natural and synthetic products. Carbazoles have taken an important part in all the existing anti-cancer drugs because of their discovery from a large variety of organisms, including bacteria, fungi, plants, and animals. In this article, we specifically explored the literature from 2012 to 2018 on the anti-tumour activities reported to carbazole derivatives and we have critically collected the most significant data. The most described carbazole anti-tumour agents were classified according to their structure, starting from the tricyclic-carbazole motif to fused tetra-, penta-, hexa- and heptacyclic carbazoles. To date, three derivatives are available on the market and approved in cancer therapy.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Carbazóis/química , Carbazóis/farmacologia , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Humanos , Estrutura Molecular , Neoplasias/patologia
14.
Eur J Med Chem ; 180: 536-545, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31344613

RESUMO

Zika virus (ZIKV) infection recently resulted in an international health emergency the Americas in and despite its high profile there is currently no approved treatment for ZIKV infection with millions of people being at risk. ZIKV is a member of Flaviviridae family which includes prominent members such as dengue virus (DENV) and West Nile virus (WNV). One of the best validated targets for developing anti-flaviviral treatment for DENV and WNV infection is the NS2B/NS3 protease. However the inhibitors reported to date have shown limited promise for further clinical development largely due to poor cellular activity. Prompted by the conserved nature of the viral NS2B/NS3 protease across flaviviruses, we envisaged that small molecule inhibitors of the ZIKVpro may be developed by applying rational design on previously reported scaffolds with demonstrated activity against other flaviviral proteases. Starting with an earlier WNVpro hit we performed a scaffold hopping exercise and discovered that certain carbazole derivatives bearing amidine groups possessed submicromolar potency and significant cellular activity against ZIKV. We successfully addressed various issues with the synthesis of novel N-substituted carbazole-based amidines thus permitting a targeted SAR campaign. The in vitro biochemical and cell-based inhibitory profiles exhibited by the lead molecule described in this work (ZIKVpro IC50 0.52 µM, EC50 1.25 µM), is among the best reported to date. Furthermore, these molecules possess capacity for further optimization of pharmacokinetics and may evolve to broad spectrum flaviviral protease inhibitors.


Assuntos
Antivirais/farmacologia , Carbazóis/farmacologia , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Zika virus/efeitos dos fármacos , Zika virus/enzimologia , Antivirais/química , Carbazóis/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteases/química , RNA Helicases/antagonistas & inibidores , RNA Helicases/metabolismo , Serina Endopeptidases/metabolismo , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismo
15.
Molecules ; 24(15)2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31344865

RESUMO

In this study, a new series of N-alkyl-3,6-dibromocarbazole and N-alkyl-5-bromoindole derivatives have been synthesized and evaluated in vitro as anti-cancer and anti-migration agents. Cytotoxic and anti-migratory effects of these compounds were evaluated in MCF-7 and MDA-MB-231 breast cancer cell lines and an insight on the structure-activity relationship was developed. Preliminary investigations of their anti-cancer activity demonstrated that several compounds have moderate antiproliferative effects on cancer cell lines with GI50 values in the range of 4.7-32.2 µM. Moreover, carbazole derivatives 10, 14, 15, 23, and 24 inhibit migration activity of metastatic cell line MDA-MB-231 in the range of 18-20%. The effect of compounds 10, 14, and 15 in extension of invadopodia and filopodia was evaluated by fluorescence microscopy and results demonstrated a reduction in actin-based cell extensions by compounds 10 and 15.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Carbazóis/química , Carbazóis/farmacologia , Indóis/química , Indóis/farmacologia , Antineoplásicos/síntese química , Carbazóis/síntese química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Humanos , Indóis/síntese química , Estrutura Molecular , Relação Estrutura-Atividade
16.
Cancer Radiother ; 23(5): 432-438, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31331844

RESUMO

Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (3 to 5% of all non-small cell lung cancers) carries a particularly high risk of central nervous system dissemination (60% to 90%). As the use of ALK inhibitors improves treatment outcomes over chemotherapy, the determent of central nervous system metastases has become an increasingly relevant therapeutic dilemma considering young age and possible extended overall survival. The goal of brain metastases management is to optimize both overall survival and quality of life, with the high priority of neurocognitive function preservation. Unfortunately in the first year on crizotinib, the pioneering ALK inhibitors, approximately one third of these patients fail in the central nervous system, which is explained by an inadequate central nervous system drug penetration through the blood-brain barrier. Central nervous system-directed radiotherapy represents the most important strategy to control intracranial disease burden and extend the survival benefit with crizotinib. The role of whole brain irradiation in the treatment of brain metastases diminishes, as this technique is associated with the risk of neurocognitive decline. Stereotactic radiotherapy represents an alternative technique that delivers ablative doses of ionizing radiation to the limited volume of oligometastatic brain disease, offering sparing of the adjacent brain parenchyma and reduced neurotoxicity. The next generation ALK inhibitors were designed to cross the blood-brain barrier more efficiently than crizotinib and achieve higher concentration in the cerebrospinal fluid, offering prominent ability to control central nervous system spread. In the phase III ALEX trial the intracranial control was significantly better with alectinib as compared to crizotinib and it translated into survival benefit. Other next generation ALK inhibitors (i.e. ceritinib, brigatinib, lorlatinib) also demonstrated promising activity in the central nervous system.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/secundário , Neoplasias Pulmonares , Neoplasias Meníngeas/secundário , Proteínas de Neoplasias/antagonistas & inibidores , Quinase do Linfoma Anaplásico/análise , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/radioterapia , Carbazóis/farmacocinética , Carbazóis/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Cisplatino/administração & dosagem , Ensaios Clínicos como Assunto , Terapia Combinada , Irradiação Craniana/efeitos adversos , Irradiação Craniana/métodos , Crizotinibe/farmacocinética , Crizotinibe/uso terapêutico , Gerenciamento Clínico , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Meníngeas/enzimologia , Neoplasias Meníngeas/radioterapia , Camundongos , Terapia de Alvo Molecular , Proteínas de Neoplasias/análise , Transtornos Neurocognitivos/etiologia , Transtornos Neurocognitivos/prevenção & controle , Estudos Observacionais como Assunto , Proteínas de Fusão Oncogênica/análise , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Pemetrexede/administração & dosagem , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Radiocirurgia/efeitos adversos , Radiocirurgia/métodos
17.
Analyst ; 144(16): 4972-4977, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31322159

RESUMO

Sulfur dioxide (SO2) plays a vital role in physiological and pathological processes. Excessive inhalation of SO2 is associated with several diseases. However, the potential physiological mechanisms of SO2 in living systems are still unclear due to the lack of an effective technique for imaging SO2 in real time in living mice. Herein, a ratiometric fluorescent probe CSP has been constructed for monitoring SO2. The novel probe CSP displayed fast sensing of SO2, excellent selectivity and photostability. More importantly, CSP was effectively employed for the detection of mitochondrial SO2 not only at the cellular level but also in zebrafish and living mice.


Assuntos
Corantes Fluorescentes/química , Mitocôndrias/metabolismo , Dióxido de Enxofre/análise , Animais , Benzotiazóis/síntese química , Benzotiazóis/química , Carbazóis/síntese química , Carbazóis/química , Fluorescência , Corantes Fluorescentes/síntese química , Células HeLa , Humanos , Camundongos Endogâmicos BALB C , Microscopia de Fluorescência/métodos , Imagem Óptica/métodos , Peixe-Zebra
18.
Anal Bioanal Chem ; 411(23): 6203-6212, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31300856

RESUMO

Cysteine is a crucial amino acid, found in a huge amount in protein-rich foods. We focused our research to determine the amount of free cysteine consumed highly in foods such as pork, beef, poultry, eggs, dairy, red peppers, soybeans, broccoli, brussels sprouts, oats, and wheat germs. A newly designed carbazole-pyridine-based fluorescent probe (CPI) has been introduced for quantitative estimation of cysteine (Cys) with a "turn on" fluorescence in some popular processed food samples chosen from our daily diet. CPI shows both naked eye and UV-visible color changes upon interaction with cysteine. The binding approach between CPI and Cys at biological pH has been thoroughly explored by UV-visible and fluorescence spectroscopy. From Job's plot analysis, 1:1 stoichiometric reaction between CPI and Cys is observed with a detection limit of 3.8 µM. NMR, ESI mass spectrometry, and time-dependent density functional theory (TD-DFT) study enlightens the formation of more stable product CPI-Cys. The "turn on" response of the probe CPI occurs due to the interruption of intra-molecular charge transfer (ICT) process upon reacting with cysteine. Moreover, CPI is a very stable, cost-effective compound and exhibits excellent real-time selectivity towards Cys over all other comparative biorelevant analytes. Interestingly, our proposed method is much advantageous as it is able to estimate cysteine predominantly by screening out other comparative biocomponents found in different protein-rich foods.


Assuntos
Carbazóis/química , Cisteína/análise , Corantes Fluorescentes/química , Análise de Alimentos/métodos , Piridinas/química , Limite de Detecção , Modelos Moleculares , Espectrometria de Fluorescência/métodos
19.
ACS Appl Mater Interfaces ; 11(31): 27574-27587, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31310503

RESUMO

A novel biscarbazol triphenylamine end-capped dendrimeric zinc(II) porphyrin (DP 5) was synthesized by click chemistry. This compound is a cruciform dendrimer that bears a nucleus of zinc(II) tetrapyrrolic macrocycle substituted at the meso positions by four identical substituents. These are formed by a tetrafluorophenyl group that possesses a triazole unit in the para position. This nitrogenous heterocyclic is connected to a 4,4'-di(N-carbazolyl)triphenylamine group by means of a phenylenevinylene bridge, which allows the conjugation between the nucleus and this external electropolymerizable carbazoyl group. In this structure, dendrimeric arms act as light-harvesting antennas, increasing the absorption of blue light, and as electroactive moieties. The electrochemical oxidation of the carbazole groups contained in the terminal arms of the DP 5 was used to obtain novel, stable, and reproducible fully π-conjugated photoactive polymeric films (FDP 5). First, the spectroscopic characteristics and photodynamic properties of DP 5 were compared with its constitutional components derived of porphyrin P 6 and carbazole D 7 moieties in solution. The fluorescence emissions of the dendrimeric units in DP 5 were more strongly quenched by the tetrapyrrolic macrocycle, indicating photoinduced energy transfer. In addition, FDP 5 film showed the Soret and Q absorption bands and red fluorescence emission of the corresponding zinc(II) porphyrin. Also, FDP 5 film was highly stable to photobleaching, and it was able to produce singlet molecular oxygen in both N,N-dimethylformamide (DMF) and water. Therefore, the porphyrin units embedded in the polymeric matrix of FDP 5 film mainly retain the photochemical properties. Photodynamic inactivation mediated by FDP 5 film was investigated in Staphylococcus aureus and Escherichia coli. When a cell suspension was deposited on the surface, complete eradication of S. aureus and a 99% reduction in E. coli survival were found after 15 and 30 min of irradiation, respectively. Also, FDP 5 film was highly effective to eliminate individual bacteria attached to the surface. In addition, photodynamic inactivation (PDI) sensitized by FDP 5 film produced >99.99% bacterial killing in biofilms formed on the surface after 60 min irradiation. The results indicate that FDP 5 film represents an interesting and versatile photodynamic active material to eradicate bacteria as planktonic cells, individual attached microbes, or biofilms.


Assuntos
Anti-Infecciosos/química , Carbazóis/química , Dendrímeros/química , Escherichia coli/crescimento & desenvolvimento , Membranas Artificiais , Metaloporfirinas/química , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento
20.
Vet Surg ; 48(7): 1318-1329, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31291009

RESUMO

OBJECTIVE: To determine the influence of short-term administration of carprofen on bone healing in dogs. STUDY DESIGN: Randomized controlled experimental study. ANIMALS: Eighteen purpose-bred sexually mature hound dogs. METHODS: Tibial osteotomies were performed, and dogs were divided into three groups: no carprofen (n = 6), 2-week administration of carprofen at 2.2 mg/kg twice daily (n = 6), and 8-week administration of carprofen at 2.2 mg/kg twice daily (n = 5). Bone healing was evaluated radiographically at 4 and 8 weeks postoperatively. Postmortem, fracture healing was assessed via biomechanical testing (three-point bending), histological cartilage:callus ratio, and bone mineral density (BMD) with quantitative computed tomography. RESULTS: No biomechanical difference was detected between dogs that received no carprofen and those that received 2 weeks of carprofen or between those that received 2 weeks vs 8 weeks of carprofen. Stiffness (P = .035) and maximum stress (P = .042) were higher in dogs that received no carprofen than in those that received 8 weeks of carprofen. Radiographic healing did not differ between dogs without carprofen and those with 2-week administration of carprofen (P = .9923). However, tibias of dogs without carprofen and those with 2-week administration of carprofen were more healed compared with those in the 8-week-carprofen group at 4 and 8 weeks after surgery (P = .0011). No treatment effect was detected by cartilage:callus ratio or BMD. CONCLUSION: Long-term administration of carprofen had a negative effect on bone healing compared with short-term or no administration of carprofen. CLINICAL SIGNIFICANCE: Nonsteroidal anti-inflammatory drugs should be used cautiously in dogs at risk for delayed bone healing, and administration should be discontinued beyond the perioperative period in dogs with fractures or osteotomies.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Carbazóis/administração & dosagem , Consolidação da Fratura/efeitos dos fármacos , Osteotomia/veterinária , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Fenômenos Biomecânicos , Densidade Óssea , Calo Ósseo , Carbazóis/uso terapêutico , Cartilagem , Cães , Esquema de Medicação , Tíbia/cirurgia
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