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1.
Eur J Med Chem ; 214: 113226, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33582387

RESUMO

Lamellarin D, a marine natural product, acts as a potent inhibitor of DNA topoisomerase I (Topo I). To modify its physicochemical property and biological activity, a series of mono- and di-glycosylated derivatives were designed and synthesized through 22-26 multi-steps. Their inhibition of human Topo I was evaluated, and most of the glycosylated derivatives exhibited high potency in inhibiting Topo I activity as well as lamellarin D. All the 15 target compounds were evaluated for their cytotoxic activities against five human cancer cell lines. The typical lamellarin derivative ZL-3 exhibited the best activity with IC50 values of 3 nM, 10 nM, and 15 nM against human lung cancer A549 cells, human colon cancer HCT116 cells and human hepatocellular carcinoma HepG2 cells. Compound ZL-1 exhibited anti-cancer activity with IC50 of 14 nM and 24 nM against human colon cancer HCT116 cells and human hepatocellular carcinoma HepG2 cells, respectively. Cell cycle analysis in MDA-MB-231 suggested ZL-3 inhibited cell growth through arresting cells at the G2/M phase of the cell cycle. Further tests showed a significant improvement in aqueous solubility of ZL-1 and ZL-7. This study suggested that glycosylation could be utilized as a useful strategy to optimize lamellarin D derivatives as Topo I inhibitors and anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Cumarínicos/farmacologia , Desenho de Fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Isoquinolinas/farmacologia , Inibidores da Topoisomerase I/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glicosilação , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Humanos , Isoquinolinas/síntese química , Isoquinolinas/química , Estrutura Molecular , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química , Células Tumorais Cultivadas
2.
Molecules ; 26(4)2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33546294

RESUMO

Coumarins possesses immeasurable antitumor potential with minimum side effects depending on the substitutions on the basic nucleus, which exhibits great prospects for antitumor drug development. In an attempt to develop novel antitumor candidates, a series of coumarin sulfonamides and amides derivatives were designed and synthetized. The majority of these derivatives showed good cytotoxic activity against MDA-MB-231 and KB cell lines, among which compound 9c was the most potent against MDA-MB-231 cells, with IC50 value of 9.33 µM, comparable to 5-fluorouracil. Further investigation revealed that compound 9c had versatile properties against tumors, including inhibition of cell migration and invasion as well as inducing apoptosis. Reactive oxygen species (ROS) assay and western blotting analysis suggested that compound 9c promoted cancer cell apoptosis by increasing ROS levels and upregulating the expression of caspase-3 in MDA-MB-231 cells. These results indicated that compound 9c could be promising lead compound for further antitumor drug research.


Assuntos
Cumarínicos , Desenho de Fármacos , Neoplasias/tratamento farmacológico , Sulfonamidas , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Cumarínicos/síntese química , Cumarínicos/química , Cumarínicos/farmacologia , Células HCT116 , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologia
3.
J Med Chem ; 63(6): 3359-3369, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32142286

RESUMO

Cytotoxic T-lymphocytes (CTLs) and natural killer cells (NKs) kill compromised cells to defend against tumor and viral infections. Both effector cell types use multiple strategies to induce target cell death including Fas/CD95 activation and the release of perforin and a group of lymphocyte granule serine proteases called granzymes. Granzymes have relatively broad and overlapping substrate specificities and may hydrolyze a wide range of peptidic epitopes; it is therefore challenging to identify their natural and synthetic substrates and to distinguish their localization and functions. Here, we present a specific and potent substrate, an inhibitor, and an activity-based probe of Granzyme A (GrA) that can be used to follow functional GrA in cells.


Assuntos
Cumarínicos/farmacologia , Corantes Fluorescentes/farmacologia , Granzimas/análise , Oligopeptídeos/farmacologia , Inibidores de Serino Proteinase/farmacologia , Linhagem Celular Tumoral , Cumarínicos/síntese química , Cumarínicos/toxicidade , Desenho de Fármacos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Granzimas/química , Humanos , Oligopeptídeos/síntese química , Oligopeptídeos/toxicidade , Inibidores de Serino Proteinase/síntese química , Inibidores de Serino Proteinase/toxicidade , Especificidade por Substrato
4.
Oxid Med Cell Longev ; 2020: 2432918, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32215169

RESUMO

The present study was directed to investigate the effect of precotreatment with (E)-N'-(1-(7-hydroxy-2-oxo-2H-chromen-3-yl) ethylidene) benzohydrazide (7-hyd.HC), a novel potent synthesized coumarin, on isoproterenol- (ISO-) induced myocardial infarction (MI) in rats. The hydrazone compound was characterized by IR, 1D, and 2D NMR analyses. Experimental induction of MI in rats was established by ISO (85 mg/kg/day, s.c) for two consecutive days (6th and 7th days). 7-hyd.HC or sintrom was given for 7 days prior and simultaneous to ISO injection. 7-hyd.HC offered a cardiopreventive effect by preventing heart injury marker leakage (LDH, ALT, AST, CK-MB, and cTn-I) from cardiomyocytes and normalizing cardiac function and ECG pattern, as well as improving lipid profile (TC, TG, LDL-C, and HDL-C), which were altered by ISO administration. Moreover, 7-hyd.HC precotreatment significantly mitigated the oxidative stress biomarkers, as evidenced by the decrease of lipid peroxidation and the increased level of the myocardial GSH level together with the SOD, GSH-Px, and catalase activities. 7-hyd.HC inhibited the cardiac apoptosis by upregulating the expression of Bcl-2 and downregulating the expression of Bax and caspase-3 genes. In addition, 7-hyd.HC reduced the elevated fibrinogen rate and better prevented the myocardial necrosis and improved the interstitial edema and neutrophil infiltration than sintrom. Overall, 7-hyd.HC ameliorated the severity of ISO-induced myocardial infarction through improving the oxidative status, attenuating apoptosis, and reducing fibrinogen production. The 7-hyd.HC actions could be mediated by its antioxidant, antiapoptotic, and anti-inflammatory capacities.


Assuntos
Anti-Inflamatórios/uso terapêutico , Benzopiranos/uso terapêutico , Cumarínicos/uso terapêutico , Hidrazonas/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Apoptose/efeitos dos fármacos , Benzopiranos/síntese química , Benzopiranos/química , Biomarcadores/metabolismo , Cumarínicos/síntese química , Cumarínicos/química , Hidrazonas/síntese química , Hidrazonas/química , Inflamação/metabolismo , Isoproterenol/toxicidade , Masculino , Estrutura Molecular , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Resultado do Tratamento
5.
Sci Rep ; 10(1): 2893, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32076009

RESUMO

The incidence of obesity-related diseases like diabetes, cardiovascular diseases, and different types of cancers shed light on the importance of dietary control as preventive and treatment measures. However, long-term dietary control is challenging to achieve in most individuals. The use of energy restriction mimetic agents (ERMAs) as an alternative approach to affect the energy machinery of cancer cells has emerged as a promising approach for cancer therapy. ERMAs limit the high need for energy in rapidly growing tumor cells, with their survival rate strongly dependent on the robust availability of energy. In this context, initial phenotypic screening of an in-house pilot compound library identified a new class of aminothiazole anchored on coumarin scaffold as potent anticancer lead drug candidates with potential activity as ERMA. The identified chemotypes were able to inhibit glucose uptake and increase ROS content in cancer cells. Compounds 9b, 9c, 9i, 11b, and 11c were highly active against colorectal cancer cell lines, HCT116 and HT-29, with half-maximal inhibitory concertation (IC50) range from 0.25 to 0.38 µM. Further biological evaluations of 9b and 9f using Western blotting, caspase activity, glucose uptake, ROS production, and NADPH/NADP levels revealed the ability of these lead drug candidates to induce cancer cell death via, at least in part, energy restriction. Moreover, the assessment of 9b and 9f synergistic activity with cisplatin showed promising outcomes. The current work highlights the significant potential of the lead compounds, 9b, and 9f as potential anticancer agents via targeting the cellular energy machinery in cancer cells.


Assuntos
Antineoplásicos/farmacologia , Cumarínicos/farmacologia , Desenho de Fármacos , Metabolismo Energético/efeitos dos fármacos , Tiazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Neoplasias Colorretais/patologia , Cumarínicos/síntese química , Cumarínicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Fase G1/efeitos dos fármacos , Glucose/metabolismo , Células HCT116 , Células HT29 , Humanos , Concentração Inibidora 50 , Espécies Reativas de Oxigênio/metabolismo , Tiazóis/síntese química , Tiazóis/química
6.
J Fluoresc ; 30(2): 317-327, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32016910

RESUMO

Herein, we report the preparation of a fluorescent sensor based on coumarin derivative for copper (II) ion sensing in CH3CN/HEPES media. 6,7-dihydroxy-3-(4-(trifluoro)methylphenyl)coumarin (HMAC) sensor was fabricated and analyzed by spectroscopic techniques. The sensor demonstrates "turn on-off" fluorescence quenching in the presence of copper (II) ions at 458 nm. A clear complex between the chemosensor HMAC and copper (II) ions was characterized by ESI-MS as well as the Job's method. Also, the limit of detection (LOD, 3σ/k) value was determined as 24.5 nM in CH3CN/HEPES (95/5, v/v) buffer media (pH = 7.0). This value is lower than the admissible level of copper (II) ions in drinking water (maximum 31.5 µM) reported by EU Water Framework Directive (WFD) and World Health Organization (WHO) guidelines. The theoretical calculations (density functional theory, DFT) have been performed for the geometric optimized structures. As a final stage, real sample analyses have successfully been performed by using HMAC, as well as ICP-OES method. The relative standard deviation for copper (II) in mineral and drinking water samples has been determined to be below 0.15% and recovery values are in the range of 95.48-109.20%.


Assuntos
Cobre/análise , Cumarínicos/química , Teoria da Densidade Funcional , Água Potável/química , Corantes Fluorescentes/química , Minerais/química , Cumarínicos/síntese química , Fluorescência , Corantes Fluorescentes/síntese química , Íons/análise , Estrutura Molecular , Espectrometria de Fluorescência
7.
Org Lett ; 22(2): 584-588, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31904969

RESUMO

We describe herein the first asymmetric total synthesis and biological evaluation of the natural PDE4 inhibitor toddacoumalone and its stereoisomers. The key step of the total synthesis is a formal asymmetric [4 + 2] cycloaddition reaction catalyzed by chiral secondary amine catalysts. A variety of pyranoquinolinones and 3-methylcrotonaldehyde are well tolerated under the optimized reaction conditions, which paved the way for further SAR studies. Further biological evaluation showed 1a' with the best PDE4 inhibitory activity (IC50 = 0.18 µM).


Assuntos
Produtos Biológicos/farmacologia , Cumarínicos/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Inibidores da Fosfodiesterase 4/farmacologia , Produtos Biológicos/síntese química , Produtos Biológicos/química , Cumarínicos/síntese química , Cumarínicos/química , Reação de Cicloadição , Humanos , Estrutura Molecular , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/química , Estereoisomerismo
8.
J Fluoresc ; 30(1): 113-120, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31897913

RESUMO

The detection and sensing of environmentally crucial metal ions has always been of great significance in various fields such as biological and environmental cycles. Our previous studies have indicated a new coumarin based lactone, Urolithin B (i.e., 3-Hydroxy[c]chromen-6-one) as a potent fluorescent probe for the selective detection of Iron (III). In order to question the extension of this application to other urolithins, we have synthesized the major urolithins that humans are exposed to through regular diet. Following the structure identifying studies, the compounds were tested in fluorescence titration to investigate their interaction with various metals. The results have indicated that each title compound is selective to interact with Iron (III) in ON-OFF mode, independent from the presence of another metal. Similar to the previous findings, the Job's plots displaying the ratio of complex formation 3:2 UROs:Fe3+ have indicated the significance of the lactone group solely.


Assuntos
Cumarínicos/química , Compostos Férricos/análise , Corantes Fluorescentes/química , Cumarínicos/síntese química , Corantes Fluorescentes/síntese química , Estrutura Molecular , Espectrometria de Fluorescência
9.
J Fluoresc ; 30(1): 27-34, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31965403

RESUMO

Using fluorescence to detect biologically relevant metals has been studied extensively due to its rapid and low detection limit ability. Sodium and potassium differentiation is significant in diagnosis of many medical conditions. For this, we designed coumarin dimers as flexible fluorescent probes using ethylene glycol units for differentiation of sodium and potassium. To our best knowledge, use of these easy-to-synthesize coumarin dimers linked through ethylene glycol units are first in the literature. In fluorescence titration experiments, diethylene glycol linked coumarin-3-carboxylate dimer is responsive for sodium ions but not for potassium ions. The driving force for the complexation of metal cation and fluorescence probes is thought to be size-matching. To further explain the phenomenon, we synthesized coumarin dimer using 1,8- octanediol as the linker, and methyl ester of coumarin-3-carboxylic acid to investigate the effect of structural changes on the fluorescence intensity. These two compounds could not differentiate the sodium and potassium. Flexible coumarin dimers as fluorophores are shown to be useful for sensing sodium cation in the presence of potassium cation.


Assuntos
Cumarínicos/química , Corantes Fluorescentes/química , Potássio/análise , Sódio/análise , Cumarínicos/síntese química , Dimerização , Corantes Fluorescentes/síntese química , Espectrometria de Fluorescência
10.
J Agric Food Chem ; 68(4): 975-981, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31891504

RESUMO

In this study, a series of coumarin derivatives containing dithioacetals were synthesized, characterized, and assessed for their anti-tobacco mosaic virus (TMV) activities. Biological tests showed that most of the title compounds exhibited significant anti-TMV biological activities; in particular, compound b21 showed good inactivating activity anti-TMV, with an EC50 of 54.2 mg/L, superior to that of ribavirin (134.2 mg/L). Transmission electron microscopy analyses showed that compound 21 severely ruptured TMV particles. The interaction of compound b21 with TMV coat protein (TMV CP) was investigated using microscale thermophoresis and molecular docking. Compound b21 exhibited a strong binding ability to TMV CP, with a value of 2.9 µM, superior to ribavirin.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Cumarínicos/síntese química , Cumarínicos/farmacologia , Antivirais/química , Proteínas do Capsídeo/química , Proteínas do Capsídeo/metabolismo , Cumarínicos/química , Desenho de Fármacos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Vírus do Mosaico do Tabaco/efeitos dos fármacos , Vírus do Mosaico do Tabaco/fisiologia
11.
J Enzyme Inhib Med Chem ; 35(1): 506-510, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31928252

RESUMO

The hypothesis that sulfocoumarin acting as inhibitors of human carbonic anhydrase (CA, EC 4.2.1.1) cancer-associated isoforms hCA IX and - hCA XII is being able to also inhibit thioredoxin reductase was verified and confirmed. The dual targeting of two cancer cell defence mechanisms, i.e. hypoxia and oxidative stress, may both contribute to the observed antiproliferative profile of these compounds against many cancer cell lines. This unprecedented dual anticancer mechanism may lead to a new approach for designing innovative therapeutic agents.


Assuntos
Antineoplásicos/farmacologia , Anidrase Carbônica IX/antagonistas & inibidores , Anidrases Carbônicas/metabolismo , Cumarínicos/farmacologia , Inibidores Enzimáticos/farmacologia , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Antígenos de Neoplasias/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Anidrase Carbônica IX/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Células MCF-7 , Estrutura Molecular , Relação Estrutura-Atividade , Tiorredoxina Dissulfeto Redutase/metabolismo , Células Tumorais Cultivadas
12.
Chem Commun (Camb) ; 56(8): 1219-1222, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31895373

RESUMO

To monitor delicate changes of biological HOCl in vivo, a new probe (OH-substituted coumarin-hemicyanine, probe 2) was synthesized for NIR and ratiometric HOCl detection. Selectivity studies indicated that the electron-donating group (OH) substituted on the indolium moiety enhanced the selectivity to detect HOCl. With HOCl, the probe showed a ratiometric fluorescence (I500/I650) with a low detection limit (49.1 nM) and a rapid response (within 2 min). In addition, probe 2 was successfully applied to visualize exogenous and endogenous HOCl in living cells and animals and exhibited a perfect mitochondria target ability. This probe has been further studied as a potential and powerful tool to probe HOCl in arthritis models.


Assuntos
Cumarínicos/química , Corantes Fluorescentes/química , Ácido Hipocloroso/análise , Indóis/química , Animais , Artrite/induzido quimicamente , Artrite/diagnóstico , Carragenina , Cumarínicos/síntese química , Cumarínicos/toxicidade , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Células Hep G2 , Humanos , Indóis/síntese química , Indóis/toxicidade , Limite de Detecção , Camundongos , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Mitocôndrias/metabolismo , Células RAW 264.7 , Espectrometria de Fluorescência/métodos , Peixe-Zebra
13.
Chem Biodivers ; 17(1): e1900462, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31788939

RESUMO

A series of coumarin-tagged ß-lactam triazole hybrids (10a-10o) were synthesized and tested for their cytotoxic activity against MDA-MB-231 (triple negative breast cancer), MCF-7 (estrogen receptor positive breast cancer (ER+)) and A549 (human lung carcinoma) cancer cell lines including one normal cell line, HEK-293 (human embryonic kidney). Two compounds 10b and 10d exhibited substantial cytotoxic effect against MCF-7 cancer cell lines with IC50 values of 53.55 and 58.62 µm, respectively. More importantly, compounds 10b and 10d were non-cytotoxic against HEK-293 cell lines. Structure-activity relationship (SAR) studies suggested that the nitro and chloro group at the C-3 position of phenyl ring are favorable for anticancer activity, particularly against MCF-7 cell lines. Furthermore, antimicrobial evaluation of these compounds revealed modest inhibition of examined pathogenic strains with compounds 10c and 10i being the most promising antimicrobial agents against Pseudomonas aeruginosa and Candida albicans, respectively.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Cumarínicos/farmacologia , Triazóis/farmacologia , beta-Lactamas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Candida albicans/efeitos dos fármacos , Candida albicans/crescimento & desenvolvimento , Proliferação de Células/efeitos dos fármacos , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Células MCF-7 , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/crescimento & desenvolvimento , Relação Estrutura-Atividade , Triazóis/química , beta-Lactamas/química
14.
Eur J Med Chem ; 186: 111900, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31771827

RESUMO

Since dual inhibitors may yield lower toxicity and reduce the likelihood of drug resistance, as well as inhibitors of HIV-1 PR and RT constitute the core of chemotherapy for AIDS treatment, we herein designed and synthesized new coumarin derivatives characterized by various linkers that exhibited excellent potency against PR and a weak inhibition of RT. Among which, compounds 6f and 7c inhibited PR with IC50 values of 15.5 and 62.1 nM, respectively, and weakly affected also RT with IC50 values of 241.8 and 188.7 µM, respectively, showing the possibility in the future of developing dual HIV-1 PR/RT inhibitors. Creative stimulation for further research of more potent dual HIV-1 inhibitors was got according to the molecular docking studies.


Assuntos
Fármacos Anti-HIV/farmacologia , Cumarínicos/farmacologia , Inibidores da Protease de HIV/farmacologia , Protease de HIV/metabolismo , Transcriptase Reversa do HIV/antagonistas & inibidores , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Linhagem Celular , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/química , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade
15.
Luminescence ; 35(2): 305-311, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31876368

RESUMO

As a type of reactive oxygen species (ROS), hydroxyl radical (·OH) is closely associated with many kinds of diseases. The present study aimed to develo p a novel OH fluorescent probe based on coumarin, a new compound that has not been previously reported. This probe exhibited good linear range and selectivity for ·OHl, and is able to avoid interference from some metal ions and other kinds of ROS (H2 O2 , O2 .- , 1 O2 , and HClO). Meanwhile, this probe has been used to evaluate the ·OH-scavenging efficiency of different compounds, such as isopropyl alcohol, cytosine, uracil, Tempo, Glutathione (GSH), and dimethyl sulfoxide (DMSO). Therefore, the present study shows that this probe not only can effectively measure the level of ·OH, but also can assess the ·OH-scavenging efficiency of different compounds. Furthermore this current study suggested that following further optimization, this probe may be potentially applied in the diagnosis of oxidative stress in human body.


Assuntos
Cumarínicos/química , Corantes Fluorescentes/química , Radical Hidroxila/análise , Cumarínicos/síntese química , Fluorescência , Corantes Fluorescentes/síntese química , Humanos , Estrutura Molecular , Espécies Reativas de Oxigênio/análise , Espectrofotometria
16.
Spectrochim Acta A Mol Biomol Spectrosc ; 228: 117710, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-31718964

RESUMO

Fluorescent sensor has been noticed in detecting system due to its sensitive, selective, operational simplicity and low cost. We designed a coumarin-connected carboxylic indolium sensor molecule that is water-soluble and cytomembrane-permeable. This infrared (IR) emitter is selectively sensitive towards cyanide detection in aqueous media according to CN- nucleophilic attack on the indole C=N function. Upon the addition of CN- anion, the color of sensor in water varied from blue to colorless by naked eyes and fluorescence quenching was observed by spectroscopic method. This was because the intramolecular charge transfer (ICT) effect occurred when the fluorescent sensor was added with CN-. The minimum detection limit of the sensor's fluorescence response to CN- is 4.44 × 10-7 mol/L. Furthermore, the cytotoxicity test shows the sensor has lower cytotoxicity, and indicates that this sensor can be utilized for practical detection of trace cyanide in wastewater.


Assuntos
Cumarínicos/química , Cianetos/análise , Indóis/química , Imagem Molecular , Água/química , Animais , Ânions , Morte Celular , Cumarínicos/síntese química , Indóis/síntese química , Melanoma Experimental/patologia , Camundongos , Modelos Moleculares , Espectroscopia de Prótons por Ressonância Magnética , Soluções , Espectrofotometria Ultravioleta
17.
Antiviral Res ; 174: 104672, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31825851

RESUMO

Spring viremia of carp virus (SVCV) is one of the most serious pathogens in aquaculture, resulting in devastating damage in cyprinid. In this study, we designed and synthesized a novel coumarin derivative (C3007) for evaluating its in vitro and in vivo anti-SVCV effects. Here, we determined that up to 25 mg/L C3007 significantly decreased SVCV protein gene expression levels in EPC cells by a maximum inhibitory rate of >95%. When C3007 was preincubated with SVCV, infectivity was significantly inhibited in vitro in a time-dependent manner, with complete inhibition at 25 mg/L. For in vivo studies, C3007 exhibited an anti-SVCV effect by substantially enhancing the survival rate of virus-infected fish via intraperitoneal injection. Although the horizontal transmission of SVCV was hindered by C3007 in a static cohabitation challenge model, it was not completely blocked, showing that the viral loads in recipient fish were obviously reduced. Thus, C3007 could potentially be used as a therapeutic agent with great potential in aquatic systems and may also be suitable for applications in pond aquaculture settings against viral transmission. Additionally, the C3007-preincubated virus induced an antiviral immune response with high levels of IFN expression, suggesting that C3007 pre-treatment could be used in vaccine development.


Assuntos
Antivirais/uso terapêutico , Carpas/virologia , Cumarínicos/uso terapêutico , Transmissão de Doença Infecciosa/veterinária , Doenças dos Peixes/tratamento farmacológico , Infecções por Rhabdoviridae/veterinária , Animais , Aquicultura , Cumarínicos/síntese química , Transmissão de Doença Infecciosa/prevenção & controle , Doenças dos Peixes/imunologia , Doenças dos Peixes/virologia , Interferons/imunologia , Rhabdoviridae/efeitos dos fármacos , Infecções por Rhabdoviridae/tratamento farmacológico , Infecções por Rhabdoviridae/imunologia , Replicação Viral/efeitos dos fármacos
18.
Anal Chim Acta ; 1094: 122-129, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31761038

RESUMO

Hypochlorite (HClO) is involved in various physiological and pathological processes as well as regulation of lysosomal functions. Thus, it is appreciated to develop efficient molecule tools for precisely detecting HClO in lysosomes. Although several lysosomal-targetable fluorogenic probes for HClO have been developed to date, they still suffered from the discounted sensing performance under lysosomal acidic condition. Herein, on the basis of the "AND" logic gate strategy, a novel dual-activatable fluorogenic probe CS has been rationally designed by simultaneously incorporating HClO recognition site and pH-sensitive group with lysosomal-targetable characteristic into a coumarin fluorophore. Different from the single-activated ones previously reported, CS exhibited good sensitivity, high specificity and fast response towards HClO under the acidic conditions but was out of operation in the neutral or alkaline environment. Importantly, it had been successfully applied for spatial-resolution imaging of exogenous or endogenous HClO in lysosomes.


Assuntos
Cumarínicos/química , Corantes Fluorescentes/química , Ácido Hipocloroso/análise , Lisossomos/metabolismo , Cumarínicos/síntese química , Cumarínicos/toxicidade , Teoria da Densidade Funcional , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Limite de Detecção , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Modelos Químicos , Espectrometria de Fluorescência/métodos
19.
Spectrochim Acta A Mol Biomol Spectrosc ; 228: 117724, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-31753645

RESUMO

By taking advantage of phenothiazine moiety as an electron-donating group, a novel donor-acceptor (D-A) type coumarin dye, PTZ-Et, was developed. The introduction of phenothiazine moiety not only caused emission red-shifting and Stokes shift enlarging, but also endowed PTZ-Et with significant aggregation-enhanced emission (AEE) features, thereby enabled PTZ-Et as a robust ratiometric fluorescent probe for HClO detection. Upon oxidation of the sulfur atom on phenothiazine into sulfoxide, PTZ-Et displayed remarkable ratiometric fluorescence response (over 150 folds variations of F534/F626) toward HClO with rapid response time (<30 s) and ultra-sensitivity (LOD = 15 nM). Additionally, the corresponding sensing mechanism of PTZ-Et for HClO was fully elucidated through the successful purification and well characterization (1H NMR, 13C NMR, HRMS, and single crystal data) of the corresponding reaction product between PTZ-Et and HClO. Significantly, PTZ-Et was capable of monitoring both exogenous and endogenous HClO in living RAW 264.7 cells by ratiometric fluorescence imaging.


Assuntos
Cumarínicos/química , Corantes Fluorescentes/química , Ácido Hipocloroso/análise , Fenotiazinas/química , Animais , Cumarínicos/síntese química , Fluorescência , Corantes Fluorescentes/síntese química , Camundongos , Microscopia de Fluorescência , Modelos Moleculares , Imagem Óptica , Fenotiazinas/síntese química , Células RAW 264.7
20.
Curr Top Med Chem ; 20(2): 153-160, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31648640

RESUMO

BACKGROUND: Glycogen synthase kinase-3 (GSK-3) is involved in the phosphorylation and inactivation of glycogen synthase. GSK-3 inhibitors have been associated with a variety of diseases, including Alzheimer´s disease (AD), diabetes type II, neurologic disorders, and cancer. The inhibition of GSK-3ß isoforms is likely to represent an effective strategy against AD. OBJECTIVE: The present work aimed to design and synthesize coumarin derivatives to explore their potential as GSK-3ß kinase inhibitors. METHODS: The through different synthetic methods were used to prepare coumarin derivatives. The GSK-3ß activity was measured through the ADP-Glo™ Kinase Assay, which quantifies the kinasedependent enzymatic production of ADP from ATP, using a coupled-luminescence-based reaction. A docking study was performed by using the crystallographic structure of the staurosporine/GSK-3ß complex [Protein Data Bank (PDB) code: 1Q3D]. RESULTS: The eleven coumarin derivatives were obtained and evaluated as potential GSK-3ß inhibitors. Additionally, in silico studies were performed. The results revealed that the compounds 5c, 5d, and 6b inhibited GSK-3ß enzymatic activity by 38.97-49.62% at 1 mM. The other coumarin derivatives were tested at 1 mM, 1 µM, and 1 nM concentrations and were shown to be inhibitor candidates, with significant IC50 (1.224-6.875 µM) values, except for compound 7c (IC50 = 10.809 µM). Docking simulations showed polar interactions between compound 5b and Lys85 and Ser203, clarifying the mechanism of the most potent activity. CONCLUSION: The coumarin derivatives 3a and 5b, developed in this study, showed remarkable activity as GSK-3ß inhibitors.


Assuntos
Cumarínicos/síntese química , Cumarínicos/farmacologia , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Cumarínicos/química , Relação Dose-Resposta a Droga , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
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