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1.
Biomed Pharmacother ; 112: 108707, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30970513

RESUMO

The synthesis and antiproliferative effect of a series of quinoline and thiazole containing coumarin analogs 12a-d and 13a-f respectively, on mice leukemic cells was performed. The chemical structures of newly synthesized compounds were confirmed by IR, 1H NMR, 13C NMR and mass spectral analysis. The result indicates that, 7-methoxy-2-oxo-2H-chromene-3-carboxylic acid [4-(4-methoxy-phenyl)-thiazol-2-yl]-amide (13f) showed potent activity against EAC and DLA cells in MTT (15.3 µM), tryphan blue (15.6 µM) and LDH (14.2 µM) leak assay with 5-fluorouracil as a standard. Further, the anti-neoplastic effect of the compound 13f was verified against Ehrlich ascites tumour by BrdU incorporation, TUNEL, FACS and DNA fragmentation assays. Experimental data showed that compound 13f induces the apoptotic cell death by activating apoptotic factors such as caspase-8 &-3, CAD, Cleaved PARP, γ-H2AX and by degrading genomic DNA of cancer cells and thereby decreasing the ascitic tumour development in mice. Besides, compound 13f was also subjected for docking studies to approve the in vitro and in vivo studies. The data revealed that the compound 13f has very good interaction with caspase 3 protein by binding with amino acid Arg 207 through hydrogen bond.


Assuntos
Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Carcinoma de Ehrlich/tratamento farmacológico , Cumarínicos/síntese química , Quinolinas/química , Tiazóis/química , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Antineoplásicos/toxicidade , Carcinoma de Ehrlich/patologia , Linhagem Celular Tumoral , Simulação por Computador , Cumarínicos/química , Cumarínicos/uso terapêutico , Cumarínicos/toxicidade , Dose Letal Mediana , Camundongos , Relação Estrutura-Atividade
2.
Chem Commun (Camb) ; 55(32): 4703-4706, 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30942238

RESUMO

A lysosome-targeting and polarity-specific fluorescent probe CPM has been rationally designed for cancer diagnosis and imaging. We have successfully shown that lysosome polarity may serve as an ubiquitious marker for cancer detection. The potential of CPM for cancer diagnosis has also been demonstrated at the levels of live cells, organs, whole animal, and clinical patient tissue samples.


Assuntos
Cumarínicos/química , Corantes Fluorescentes/química , Lisossomos/metabolismo , Neoplasias/diagnóstico , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/síntese química , Cumarínicos/toxicidade , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Humanos , Camundongos , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos
3.
Anal Chim Acta ; 1058: 136-145, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-30851847

RESUMO

Based on conjugate addition-cyclization reaction of Cys with acrylate and subsequent 1,6-elimination of p-hydroxybenzyl moiety, a novel colorimetric and ratiometric fluorescent probe 1 was designed and synthesized. Upon addition of Cys to the solution of 1, the absorption spectra changed from 508 nm to 452 nm (Δ56 nm) and afforded visible color change from pink to yellow. Meanwhile, the emission spectra shifted from 644 nm to 539 nm (Δ105 nm) with remarkable changes in the emission ratio of F539 nm/F644 nm (R/R0 up to 760-fold), accompanying with an obvious fluorescence change from orange to green under illumination with a 365 nm UV lamp. In addition, 1 exhibited a large Stokes shift (136 nm), high sensitivity (detection limit of 46.7 nM), and excellent selectivity to Cys over Hcy and GSH. Moreover, 1 can discriminate Cys from Hcy and GSH by fluorescence spectra, even obvious visible and fluorescence color changes. Importantly, 1 can be used to image Cys in living cells by dual emission channels.


Assuntos
Acrilatos/química , Cumarínicos/química , Cisteína/análise , Corantes Fluorescentes/química , Acrilatos/síntese química , Acrilatos/toxicidade , Colorimetria/métodos , Cumarínicos/síntese química , Cumarínicos/toxicidade , Ciclização , Cisteína/química , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Células HeLa , Humanos , Limite de Detecção , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos
4.
Environ Toxicol ; 34(6): 768-776, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30848542

RESUMO

Osthole (Ost) is often used in treatment for cancer, inflammation and rheumatism in clinic. However, Ost-induced liver injury has been reported. In this study, we aim to investigate the possible mechanism of Ost-induced hepatotoxicity in human normal liver cells (L02). When cells were exposed to Ost, the cell viability was decreased and apoptosis rate increased, the intracellular markers of oxidative stress were changed. Simultaneously, Ost altered apoptotic related proteins levels, including Bcl-2, Bax, Cleaved-Caspase-9/-8/-3, and Pro-Caspase-3/-8. In addition, Ost enhanced the levels of endoplasmic reticulum (ER) stress proteins (GRP78/Bip, CHOP, Caspase-4, IRE1α, PERK, JNK, P-JNK, and ATF4), decreased the cell proliferation and cycle-associated protein (Phospho-Histone H3, P-Cdc25C, Cdc25C, P-Cdc2, Cdc2, and Cyclin B1) level. The results show that Ost has toxic effects on L02 cells. Furthermore, it induces apoptosis by inhibiting cell proliferation, arresting cell cycle at the G2/M phase and activating ER stress.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cumarínicos/toxicidade , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fígado/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Técnicas de Cultura de Células , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Fígado/metabolismo , Fígado/patologia
6.
Toxicol Lett ; 303: 67-71, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30599194

RESUMO

The hepatic cytochrome p450 enzymes 1 A, 2A19 and 2E1 is very important for the elimination of skatole from the body of pigs. Impaired skatole metabolism, results in skatole accumulation, which give rise to off flavor of the meat. Several metabolites of skatole has been identified, however the role of these metabolites in the inhibition of the skatole metabolizing enzymes are not documented. Using microsomes from pigs and fish, we determined the ability of several skatole metabolites to inhibit CYP1 A, CYP2A19 and CYP2E1 dependent activity. Our results show that 2-aminoacetophenone is an inhibitor of porcine CYP2A19 and CYP2E1 activity, but not the piscine orthologues. In conclusion, there is species specific differences in the inhibition of CYP1 A and CYP2A19 dependent metabolism of probe substrates. This is relevant to the evaluation of different model systems and to the reduction of off flavor of meat.


Assuntos
Inibidores do Citocromo P-450 CYP2E1/toxicidade , Fígado/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Escatol/toxicidade , Acetofenonas/toxicidade , Animais , Cumarínicos/toxicidade , Citocromo P-450 CYP1A1/antagonistas & inibidores , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP2E1/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Peixes , Fígado/metabolismo , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Nitrofenóis/toxicidade , Oxazinas/toxicidade , Carne Vermelha/análise , Alimentos Marinhos/análise , Especificidade da Espécie , Suínos
7.
Pharmacology ; 103(3-4): 120-127, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30544127

RESUMO

Isofraxidin is a Coumarin compound widely distributed in plants, such as the Umbelliferae or Chloranthaceae, and it possesses numerous pharmacological activities. However, whether isofraxidin affects the activity of human liver cytochrome P450 (CYP) enzymes remains unclear. In this study, the inhibitory effects of isofraxidin on the 8 human liver CYP isoforms (i.e., 1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19, and 2C8) were investigated in vitro using human liver microsomes. The results showed that isofraxidin inhibited the activity of CYP1A2, 3A4, and 2E1, with IC50 values of 23.01, 15.49, and 15.98 µmol/L, respectively, but that other CYP isoforms were not affected. Enzyme kinetic studies showed that isofraxidin was not only a noncompetitive inhibitor of CYP3A4 but also a competitive inhibitor of CYP1A2 and 2E1, with Ki values of 7.91, 10.14, and 9.30 µmol/L, respectively. In addition, isofraxidin is a time-dependent inhibitor for CYP3A4 with Kinact/KI value of 0.047/12.33 µmol/L-1min-1. The in vitro studies of isofraxidin with CYP isoforms indicate that isofraxidin has the potential to cause pharmacokinetic drug interactions with other coadministered drugs metabolized by -CYP1A2, 3A4, and 2E1. Further clinical studies are needed to evaluate the significance of this interaction.


Assuntos
Cumarínicos/farmacologia , Citocromo P-450 CYP1A1/antagonistas & inibidores , Citocromo P-450 CYP2E1 , Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450/farmacologia , Fígado/efeitos dos fármacos , Cumarínicos/toxicidade , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP2E1/metabolismo , Inibidores do Citocromo P-450 CYP2E1/farmacologia , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/farmacologia , Inibidores das Enzimas do Citocromo P-450/toxicidade , Interações de Medicamentos , Humanos , Cinética , Fígado/enzimologia , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia
8.
Chem Commun (Camb) ; 54(85): 12093-12096, 2018 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-30298871

RESUMO

A robust fluorescent probe CTPA has been rationally designed for cancer diagnosis by monitoring lipid drop (LD) polarity and number variation. With the outstanding properties of CTPA, we have shown that the diagnosis of cancer can be achieved not only at the cellular levels but also in organs and living mice for the first time.


Assuntos
Cumarínicos/química , Corantes Fluorescentes/química , Gotículas Lipídicas/metabolismo , Neoplasias/diagnóstico por imagem , Animais , Linhagem Celular Tumoral , Cumarínicos/síntese química , Cumarínicos/toxicidade , Desenho de Drogas , Feminino , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Humanos , Camundongos Endogâmicos BALB C , Imagem Óptica/métodos
9.
Chem Commun (Camb) ; 54(85): 12010-12013, 2018 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-30204171

RESUMO

Using the conformational restraint strategy, we developed a hydrazonate-derived coumarin into a lysosome targeting probe for imaging native formaldehyde at the subcellular level. Using this probe, we observed the overproduction of formaldehyde in lysosomes when cells were treated with endoplasmic reticulum (ER) stress inducers, suggesting the involvement of formaldehyde in protein misfolding.


Assuntos
Cumarínicos/química , Corantes Fluorescentes/química , Formaldeído/metabolismo , Hidrazonas/química , Lisossomos/metabolismo , Linhagem Celular , Cumarínicos/síntese química , Cumarínicos/toxicidade , Estresse do Retículo Endoplasmático , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Formaldeído/análise , Humanos , Hidrazonas/síntese química , Hidrazonas/toxicidade , Limite de Detecção , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Conformação Molecular , Dobramento de Proteína/efeitos dos fármacos
10.
Chem Commun (Camb) ; 54(81): 11387-11390, 2018 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-30191239

RESUMO

In this study, we developed a multi-signal mitochondria-targeted fluorescent probe (NIR-Cys) for simultaneous detection of Cys and its metabolite, SO2. In the design of the probe, the acrylate group and the C[double bond, length as m-dash]C of the coumarin ring were used as the recognizing moiety for Cys and SO2, respectively. The probe exhibited high sensitivity, excellent specificity, and fast response. NIR-Cys was found to precisely target and visualize Cys metabolism in mitochondria of living cells with a multi-fluorescence signal. This probe is expected to be a useful tool for understanding Cys metabolism.


Assuntos
Acrilatos/química , Cumarínicos/química , Cisteína/análise , Corantes Fluorescentes/química , Mitocôndrias/metabolismo , Dióxido de Enxofre/análise , Acrilatos/síntese química , Acrilatos/metabolismo , Acrilatos/toxicidade , Animais , Linhagem Celular Tumoral , Cumarínicos/síntese química , Cumarínicos/metabolismo , Cumarínicos/toxicidade , Cisteína/metabolismo , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/metabolismo , Corantes Fluorescentes/toxicidade , Humanos , Limite de Detecção , Fígado/metabolismo , Camundongos , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Sulfitos/análise , Sulfitos/química , Dióxido de Enxofre/metabolismo , Peixe-Zebra
12.
Spectrochim Acta A Mol Biomol Spectrosc ; 204: 590-597, 2018 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-29980060

RESUMO

On base of the good optical properties of coumarin and fluorescein, we designed and synthesized two coumarin/fluorescein-fused fluorescent dyes (CF dyes), which enlarged the emission wavelength and increased the Stokes shift of fluorescein moiety. The corresponding optical properties of CF dyes were investigated in detail. CF dyes could easily introduce other groups to design different functional molecules. CF dyes also exhibited rapid and sensitive responses to pH values in the range of 4.0-7.4 through the characterization of absorption and fluorescence spectra in buffer solution. More importantly, CF ethyl ester dye (CFE dye) not only showed good cell membrane permeability and low cytotoxicity, but also had the ability to rapidly monitor mitochondrial pH changes in living cells.


Assuntos
Cumarínicos/análise , Fluoresceína/análise , Corantes Fluorescentes/análise , Mitocôndrias/química , Cumarínicos/química , Cumarínicos/toxicidade , Fluoresceína/química , Fluoresceína/toxicidade , Corantes Fluorescentes/química , Corantes Fluorescentes/toxicidade , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Mitocôndrias/metabolismo , Espectrometria de Fluorescência
13.
J Sep Sci ; 41(16): 3328-3338, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29957847

RESUMO

Genkwa Flos, a famous traditional Chinese medicine has been reported to have significant hepatotoxicity. A high-throughput and reliable method was established to explore potential toxic components by high-performance liquid chromatography coupled with a Q Exactive high-performance benchtop quadrupole-Orbitrap mass spectrometer. A total of 68 compounds including 22 chemical components and 46 metabolites were tentatively identified based on the accurately measured mass value, retention time, and fragmentation pattern. Besides, the metabolic pathways of main components in Genkwa Flos were also illustrated. The results indicated that hydroxylation, demethylation, methylation, glucuronidation, sulfation, cysteine conjugation, and glutathione conjugation participated in the metabolic reactions of Genkwa Flos. Moreover, 12 Genkwa Flos chemical components and 26 metabolites were detected in cell lysate, which were considered as the bound components to HL-7702 cells. In view of cell affinity theory, these compounds were preliminarily deduced to be potential toxic ingredients for the hepatotoxicity induced by Genkwa Flos. The results demonstrated that the developed method was a very feasible and efficient approach for the components identification even in the complex matrix. In conclusion, this study will provide a deep insight into the toxic substances of Genkwa Flos and lay a chemical basis for in-depth toxic studies on Genkwa Flos hepatotoxicity.


Assuntos
Medicamentos de Ervas Chinesas/toxicidade , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Cumarínicos/sangue , Cumarínicos/metabolismo , Cumarínicos/toxicidade , Diterpenos/sangue , Diterpenos/metabolismo , Diterpenos/toxicidade , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/metabolismo , Flavonoides/sangue , Flavonoides/metabolismo , Flavonoides/toxicidade , Glicosídeos/sangue , Glicosídeos/metabolismo , Glicosídeos/toxicidade , Humanos , Lignanas/sangue , Lignanas/metabolismo , Lignanas/toxicidade , Masculino , Espectrometria de Massas , Medicina Tradicional Chinesa , Estrutura Molecular , Ratos , Ratos Sprague-Dawley
14.
Toxicol In Vitro ; 51: 50-53, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29747020

RESUMO

Temporary consolidants, such as cyclododecane, menthol, coumarin, and ethyl maltol, are proved to be effective for urgent conservation in archaeological field. However, the safety of these temporary consolidants is still unknown although they are always heavily used in archaeological field. Thus reports on the toxicity of these temporary consolidants are limited. Here, a zebrafish model was used for safety evaluation of these four temporary consolidants. In the present study, four temporary consolidants, including cyclododecane, menthol, coumarin, and ethyl maltol, at different concentrations were incubated with zebrafish embryos, and their biological toxic effects were firstly evaluated. It was shown that embryo exposure to temporary consolidants resulted in an increased mortality and malformation rate, and a decreased hatching rate. The order of embryo toxicity of the four types of temporary consolidants tested was menthol > coumarin > ethyl maltol > cyclododecane. Although the embryo toxicity of cyclododecane was minimal, some studies have indicated that this temporary consolidant could be bioaccumulated. The results also suggested that the zebrafish embryos can serve as a reliable model for the evaluation of embryo toxicity of temporary consolidants, as this model could offer the possibility to perform the rapid, medium throughput, cost-effective analyses.


Assuntos
Cumarínicos/toxicidade , Cicloparafinas/toxicidade , Embrião não Mamífero/efeitos dos fármacos , Mentol/toxicidade , Pironas/toxicidade , Peixe-Zebra , Animais , Embrião não Mamífero/anormalidades , Coluna Vertebral/anormalidades , Coluna Vertebral/efeitos dos fármacos , Testes de Toxicidade/métodos , Peixe-Zebra/anormalidades
15.
Inorg Chem ; 57(11): 6340-6348, 2018 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-29792415

RESUMO

Antibacterial agents with two-photon absorption are expected to play a significant role in biomedical science. Herein, two novel organotin complexes, HLSn1 and HLSn2, based on coumarin were designed, synthesized, and systematically investigated. It was found that these complexes possessed suitable two-photon-active cross sections in the near-infrared region. Moreover, complex HLSn1 could efficiently inhibit the growth of Gram-negative Escherichia coli and Gram-positive Bacillus subtilis, especially the latter with a minimum inhibitory concentration (MIC; 90%) of 2 ± 0.14 µg mL-1, which is lower than that of Kanamycin (Kana, 8 ± 0.42 µg mL-1). Importantly, two-photon imaging and superresolution development of bacterial stain revealed that complex HLSn1 can react with bacterial membranes, producing reactive oxygen species (ROS) and leading to cell death. These outcomes provide promising applications in the superresolution bacteria imaging, diagnostics, and treatment of bacterial infectious.


Assuntos
Antibacterianos/farmacologia , Complexos de Coordenação/farmacologia , Cumarínicos/farmacologia , Compostos Orgânicos de Estanho/farmacologia , Estanho , Antibacterianos/química , Antibacterianos/toxicidade , Bacillus subtilis/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , Cumarínicos/química , Cumarínicos/toxicidade , Escherichia coli/efeitos dos fármacos , Fluorescência , Testes de Sensibilidade Microbiana , Estrutura Molecular , Imagem Óptica , Compostos Orgânicos de Estanho/química , Compostos Orgânicos de Estanho/toxicidade
16.
Med Chem ; 14(6): 573-584, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29669503

RESUMO

BACKGROUND: Neglected diseases are becoming more prevalent due to globalization. This has inspired active research in the development of new drugs for the treatment of parasitic diseases such as Chagas disease. OBJECTIVES: With the aim of finding new trypanocidal agents, we report the in vitro evaluation of a new series of 3-amidocoumarins with or without hydroxyl substituents at position 4 of the coumarin ring. METHODS: Electrochemical and biological assays were performed in order to assess the antioxidant and trypanocidal potential of these compounds and to better understand the mechanisms involved in their activity. RESULTS: Most of the studied compounds showed high trypanocidal activity against both epimastigote and trypomastigote forms, with IC50 values in the low micromolar range. Some of them have greater activity and selectivity than the reference compound, nifurtimox. CONCLUSION: Compound 2 is the most active of this series, being also non-cytotoxic against murine RAW 264.7 macrophages. Electrochemical and radical scavenging experiments were carried out, providing new information about the profile of the best derivatives, and the potential therapeutic application of the new 3-amidocoumarins.


Assuntos
Amidas/farmacologia , Antioxidantes/farmacologia , Cumarínicos/farmacologia , Tripanossomicidas/farmacologia , Amidas/síntese química , Amidas/química , Amidas/toxicidade , Animais , Antioxidantes/síntese química , Antioxidantes/química , Antioxidantes/toxicidade , Cromanos/farmacologia , Cumarínicos/síntese química , Cumarínicos/química , Cumarínicos/toxicidade , Técnicas Eletroquímicas , Radicais Livres/química , Camundongos , Modelos Químicos , Estrutura Molecular , Nifurtimox/farmacologia , Testes de Sensibilidade Parasitária , Células RAW 264.7 , Tripanossomicidas/síntese química , Tripanossomicidas/química , Tripanossomicidas/toxicidade
17.
Chem Pharm Bull (Tokyo) ; 66(3): 309-318, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29491264

RESUMO

The reactivity of compounds 2-(1-(2-chloroacetyl)-1H-benzo[d]imidazol-2-yl)acetonitrile 2 and 3-(1-(2-chloroacetyl)-1H-benzo[d]imidazol-2-yl)-2H-chromen-2-one 8 towards different chemical reagents were studied and a series of novel benzimidazole derivatives were obtained (2-6a-d and 8-12a-d). Moreover, in vitro growth inhibitory effect of the newly synthesized compounds were evaluated in term of [IC50 µM] against the six cancer cell lines, human lung carcinoma (A549), lung cancer (H460), human colorectal (HT29), gasteric cancer cell (MKN-45), glioma cell line (U87MG) and cellosaurus cell line (SMMC-7721) where foretinib was used as standard reference. The results showed that compounds 2 (only for A549 cell line), 3a, 4, 6c, 6d, 8, 9a, 9e and 9f were the most active compounds towards the six cancer cell lines. On the other hand, the toxicity of these most potent compounds against shrimp larvae indicated that compounds 3a, 4, 6d, 9e and 9f were non toxic while compounds 6c and 8 were very toxic and compounds 2 and 9a were harmful against the tested organisms.


Assuntos
Antineoplásicos/síntese química , Benzimidazóis/química , Cumarínicos/química , Tiazóis/química , Tiofenos/química , Anilidas/toxicidade , Animais , Antineoplásicos/química , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cumarínicos/síntese química , Cumarínicos/toxicidade , Decápodes (Crustáceos)/crescimento & desenvolvimento , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Quinolinas/toxicidade , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/toxicidade , Tiofenos/síntese química , Tiofenos/toxicidade
18.
Regul Toxicol Pharmacol ; 94: 75-82, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29339246

RESUMO

Neoflavonoids, which are classified as 4-arylcoumarin (neoflavone), 3,4-dihydro-4-arylcoumarin and neoflavene, have been the subject of a number of studies with respect to their therapeutic potential and, despite promising in vitro, ex vivo and in vivo pharmacological activities, there is a lack of studies demonstrating their toxicological properties. Therefore, this study aims to evaluate the acute (14 days) and repeated-dose (28 days) toxicity of synthetic neoflavonoid 7-acetoxy-4-aryl-3,4-dihydrocoumarin in Swiss mice through parameters related to changes in body weight, food and water intake, hematological and biochemical parameters. Toxicity studies using acute doses (300 and 2000 mg/kg) and repeated doses (250, 500 and 1000 mg/kg) orally were carried out as per Organization for Economic Co-operation and Development (OECD) guidelines 423 and 407, respectively. Based on the results of this study, treatment with 7-acetoxy-4-aryl-3,4-dihydrocoumarin was found to not cause clinical adverse symptoms and mortality in any animal used in the acute and repeated-dose toxicity study. In addition, no significant changes were observed in body weight and internal organs, food and water intake, hematological and biochemical parameters, compared to control group. Therefore, these results provide an initial understanding regarding the toxicity profile of 7-acetoxy-4-aryl-3,4-dihydrocoumarin, which can be considered a neoflavonoid with toxicity seen at doses higher than 2000 mg/kg in Swiss mice.


Assuntos
Cumarínicos/toxicidade , Animais , Artemia/efeitos dos fármacos , Feminino , Masculino , Camundongos , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda
19.
Curr Med Chem ; 25(12): 1446-1476, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28464781

RESUMO

BACKGROUND: Coumarins are polyphenolic compounds that are often used to treat inflammatory conditions in complementary and alternative medicine. OBJECTIVE: In this study, we reviewed reports of in vivo and in vitro experimental modelbased approaches investigating the potential anti-inflammatory properties of coumarins. METHODS: A literature search of PUBMED, MEDLINE, Web of Science, and Scopus was performed covering the period from 1 January 2005 to 31 December 2015. The keywords used to search were 'anti-inflammatory' and 'coumarin' and 'in vivo' or 'in vitro'. This search identified 425 article titles. RESULTS: Of the 425 article titles, 127 full-text articles were reviewed, and 69 of them were included in the analysis. Most of the studies (81.2%) used in vitro assays. The studies focused on cytokines such as tumour necrosis factor (TNF), interleukin (IL)-6, and IL-1-ß (55.1%), as well as oedema (46.5%), nitric oxide (NO, 23.2%), oxidative stress (21.7%), inflammatory cells (21.7%), nuclear factor (NF)-κB (24.6%), mitogen-activated protein kinase (MAPK, 13%), myeloperoxidase (MPO, (15.9%), cyclooxygenase (COX)-2 (14.5%), prostaglandin E2 (PGE2, 8.7%), 5-lipoxygenase (LOX, 4.3%), and adhesion molecules (7.2%). Coumarins inhibited all these parameters except for IL-10, nuclear factor erythroid 2 (NFE2)-related-factor 2 (Nrf2), and regulatory T cell (Treg) differentiation. CONCLUSION: In vitro methods were the most commonly used to study the antiinflammatory effects of coumarins. The results showed that coumarins exerted antiinflammatory and antioxidant activities by inhibiting NF-κB, nuclear factor of activated T cells (NFAT), retinoic acid-related orphan receptor γτ (RORγτ), and MAPK and increasing Nrf2 activation. These results suggest that coumarins could be important candidates for the development of novel anti-inflammatory therapeutic drugs.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Cumarínicos/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/toxicidade , Linhagem Celular Tumoral , Cumarínicos/farmacologia , Cumarínicos/toxicidade , Citocinas/antagonistas & inibidores , Feminino , Humanos , Masculino , Transdução de Sinais/efeitos dos fármacos
20.
Int J Mol Sci ; 18(12)2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29215575

RESUMO

Effective DNA repair enables cancer cells to survive DNA damage induced by chemotherapeutic or radiotherapeutic treatments. Therefore, inhibiting DNA repair pathways is a promising therapeutic strategy for increasing the efficacy of such treatments. In this study, we found that dihydrocoumarin (DHC), a flavoring agent, causes deficiencies in double-stand break (DSB) repair and prolonged DNA damage checkpoint recovery in yeast. Following DNA damage, Rad52 recombinase was revealed to be inhibited by DHC, which results in deficiencies in DSB repair and prolonged DNA damage checkpoint recovery. The deletion of RPD3, a class I histone deacetylase (HDAC), was found to mimic DHC-induced suppression of Rad52 expression, suggesting that the HDAC inhibitor activity of DHC is critical to DSB repair and DNA damage sensitivity. Overall, our findings delineate the regulatory mechanisms of DHC in DSB repair and suggest that it might potentially be used as an inhibitor of the DNA repair pathway in human cells.


Assuntos
Cumarínicos/toxicidade , Dano ao DNA , Aromatizantes/toxicidade , Inibidores de Histona Desacetilases/toxicidade , Proteína Rad52 de Recombinação e Reparo de DNA/antagonistas & inibidores , Proteínas de Saccharomyces cerevisiae/antagonistas & inibidores , Cumarínicos/farmacologia , Aromatizantes/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Reparo de DNA por Recombinação , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo
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