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1.
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
2.
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
3.
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
4.
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
5.
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
6.
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
7.
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
8.
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
9.
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
10.
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
11.
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
12.
Talanta ; 204: 592-601, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31357339

RESUMO

Development of conjugated polymers with fluorescence sensing characteristics has received close attention from researchers in fields of environmental protection, biosensing and toxins detection on food. In this paper, novel polyaniline derivatives of poly(9-methyl-9H-carbazol-3-amine) and poly(9,9-dihexyl-9H-fluoren-2-amine) are prepared by facile chemical polymerization. Then they are characterized with NMR (Nuclear Magnetic Resonance), GPC (Gel Permeation Chromatography), XRD (X-Ray Diffraction), FT-IR (Fourier Transform Infrared spectroscopy), FL (Fluorescence spectrometry) and UV-vis (Ultraviolet-visible spectroscopy) characterizations and further applied to the fluorescence detection of different acids and amines. Moreover, the obtained poly(9-methyl-9H-carbazol-3-amine) displays excellent fluorescence properties in the detection for both acids and amines. Besides, this poly(9-methyl-9H-carbazol-3-amine) can not only be used for fluorescence detection in solution, but also can be prepared into solid state and applied in the gas phase fluorescence detection. This work has greatly expanded the scope of application to these polyaniline derivatives materials, opening a new path for the researches on multi-functional chemosensor.


Assuntos
Compostos de Anilina/química , Carbazóis/química , Fluorenos/química , Corantes Fluorescentes/química , Compostos de Anilina/síntese química , Carbazóis/síntese química , Etilenodiaminas/análise , Etilenodiaminas/química , Fluorenos/síntese química , Fluorescência , Corantes Fluorescentes/síntese química , Ácido Clorídrico/análise , Ácido Clorídrico/química , Ligações de Hidrogênio , Limite de Detecção , Metilaminas/análise , Metilaminas/química , Ácido Nítrico/análise , Ácido Nítrico/química , Reprodutibilidade dos Testes , Espectrometria de Fluorescência/métodos
13.
Org Biomol Chem ; 17(25): 6277-6283, 2019 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-31192345

RESUMO

Interaction analysis in vivo greatly promotes the analyses and understanding of biological functions. The interaction between DNA and peptides or proteins is very important in terms of readout and amplifying information from genomic DNA. In this study, we designed and synthesized a photo-cross-linkable amino acid, l-3-cyanovinlycarbazole amino acid (l-CNVA), to double-stranded DNA. Reversible photo-cross-linking between DNA and peptides containing CNVA, having 3-cyanovinylcarbazole moieties capable of photo-cross-linking to nucleic acids, was demonstrated. As a result, it was shown that the GCN4 peptide, containing CNVA, can be photo-cross-linked to DNA, and its adduct was photo-split into the original peptide and DNA with 312 nm-irradiation. This is the first report that reversibly manipulates photo-crosslinking between double stranded DNA and peptides. In addition, this reversible photo-cross-linking, using l-CNVA, is faster and with higher yield than that using diazirine and psoralen.


Assuntos
Aminoácidos/química , Carbazóis/química , Reagentes para Ligações Cruzadas/química , DNA/química , Peptídeos/química , Aminoácidos/efeitos da radiação , Carbazóis/efeitos da radiação , Reagentes para Ligações Cruzadas/efeitos da radiação , Peptídeos/efeitos da radiação , Conformação Proteica em alfa-Hélice , Raios Ultravioleta
14.
Curr Microbiol ; 76(9): 982-987, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31168648

RESUMO

Members of marine Actinobacteria have been highly regarded as potentially important sources of antimicrobial compounds. Here, we isolated a strain of Actinobacteria, SZJ61, and showed that it inhibits the in vitro growth of fungi pathogenic to plants. This new isolate was identified as Streptomyces luteoverticillatus by morphological, biochemical and genetic analyses. Antifungal compounds were isolated from S. luteoverticillatus strain SZJ61 and characterized as carbazomycin B by nuclear magnetic resonance spectra. We then sequenced the genome of the S. luteoverticillatus SZJ61 strain, which consists of only one 7,367,863 bp linear chromosome that has a G+C content of 72.05%. Thirty-five putative biosynthetic gene clusters for secondary metabolites, including a variety of bioactive products, were found. Mining of the genome sequence information revealed the putative biosynthetic gene cluster of carbazomycin B. This genomic information is valuable for interpreting the biosynthetic mechanisms of diverse bioactive compounds that have potential applications in the pharmaceutical industry.


Assuntos
Genoma Bacteriano , Streptomyces/genética , Streptomyces/metabolismo , Antifúngicos/química , Antifúngicos/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Composição de Bases , Carbazóis/química , Carbazóis/metabolismo , China , Sedimentos Geológicos/microbiologia , Família Multigênica , Filogenia , Streptomyces/classificação , Streptomyces/isolamento & purificação
15.
Spectrochim Acta A Mol Biomol Spectrosc ; 221: 117175, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31158770

RESUMO

As an effective lysosomal biomarker for oxidative stress status, cysteine (Cys) plays an important role in lysosomal proteolysis. Herein, we report the first lysosome-targetable fluorescence probe (MCAB) for Cys-selective detection based on nucleophilic addition reaction of sulfhydryl toward a α, ß-unsaturated ketone and demonstrate its application to lysosomal-targetable imaging. MCAB is designed based on a α, ß-unsaturated ethanoylcarbazole as the fluorophore and the thiols reaction site, and a methylcarbitol unit as a lysosome-targetable group. Upon reacting with Cys, this probe turns on highly specific fluorescence signals linearly proportional to Cys concentrations over the range of 0-300 µM. MCAB detects Cys with a rapid response time (within 12 min) and low limit of detection (0.38 µM). MCAB is highly selective to Cys over other similar biothiols including homocysteine (Hcy) and glutathione (GSH). Moreover, it also exhibits significant lysosomal-targetable ability, which is ideal for lysosomal Cys-selective imaging. Using MCAB, we have successfully visualized the fluctuation endogenous Cys in lysosomes under oxidative stress status in real-time.


Assuntos
Cisteína/análise , Corantes Fluorescentes/química , Lisossomos/metabolismo , Imagem Molecular/métodos , Estresse Oxidativo , Carbazóis/química , Linhagem Celular Tumoral , Corantes Fluorescentes/síntese química , Humanos , Peróxido de Hidrogênio/farmacologia , Concentração de Íons de Hidrogênio , Limite de Detecção , Lipopolissacarídeos/toxicidade , Lisossomos/efeitos dos fármacos , Microscopia de Fluorescência/instrumentação , Estresse Oxidativo/efeitos dos fármacos , Espectrometria de Fluorescência , Espectrofotometria Ultravioleta , Tempo
16.
J Agric Food Chem ; 67(26): 7512-7525, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31180659

RESUMO

Recent observations on the emergence of drug-resistant plant pathogenic bacteria have highlighted and elicited an acute campaign to develop novel, highly efficient antibiotic surrogates for managing bacterial diseases in agriculture. Thus, a type of racemic and chiral carbazole derivative containing an isopropanolamine pattern was systematically synthesized to discover low-cost and efficient antibacterial candidates. Screening results showed that compounds 2f, 6c, and 2j could significantly suppress the growth of tested plant pathogens, namely Xanthomonas oryzae pv oryzae, X. axonopodis pv citri, and Pseudomonas syringae pv actinidiae, and provided the corresponding EC50 values of 1.27, 0.993, and 0.603 µg/mL, which were significantly better than those of existing commercial drugs. In vivo studies confirmed their prospective applications for controlling plant bacterial diseases. Label-free quantitative proteomics analysis indicated that compound 2f could dramatically induce the up- and down-regulation of a total of 247 differentially expressed proteins, which was further validated by the parallel reaction monitoring technique. Moreover, fluorescence spectra and SEM images were obtained to further explore the antibacterial mechanism.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Carbazóis/química , Carbazóis/farmacologia , Doenças das Plantas/microbiologia , Propanolaminas/química , Pseudomonas syringae/efeitos dos fármacos , Xanthomonas/efeitos dos fármacos , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Testes de Sensibilidade Microbiana , Proteômica , Pseudomonas syringae/química , Pseudomonas syringae/genética , Pseudomonas syringae/metabolismo , Relação Estrutura-Atividade , Xanthomonas/química , Xanthomonas/genética , Xanthomonas/metabolismo
17.
Analyst ; 144(14): 4288-4294, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31183481

RESUMO

Lysosomes are acidic organelles containing many hydrolytic enzymes responsible for degrading macromolecules. Aberrant lysosomal pH changes are known to associate with lysosomal dysfunctions linking to various diseases including cancer and neurodegenerative disorders. Thus, it is of paramount importance to monitor lysosomal pH changes in order to investigate the pathological conditions. We report herein two novel, highly sensitive and fast responsive carbazole-based ratiometric fluorescent probes with different emission wavelengths, namely MCDBI and MCDI for lysosomal pH detection and imaging. Importantly, the MCDBI and MCDI probes bearing indole and benzoindoles as acid-sensing sites exhibit pKa values of 4.26 and 4.51, respectively, which are ideal for the quantitative analysis of lysosomal pH changes in living cells. These probes exhibited a strong pH-dependent behavior and responded linearly and rapidly to minor pH fluctuations. Moreover, the two biocompatible probes are highly lysosomal targeting, sensitive towards H+ over metal ions and some bioactive molecules, and exhibit excellent photostability and good reversibility. These probes have excellent cell membrane permeability and are further applied successfully to monitor lysosomal pH fluctuations in the lysosomes of HepG2 cells.


Assuntos
Carbazóis/química , Corantes Fluorescentes/química , Lisossomos/metabolismo , Carbazóis/toxicidade , Fluorescência , Corantes Fluorescentes/toxicidade , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos
18.
Sci Total Environ ; 686: 1039-1048, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31200302

RESUMO

2,7-Dibromocarbazole (2,7-DBCB) and 3,6-dibromocarbazole (3,6-DBCB) are emerging environmental pollutants, being potentially high risks to human health. In this study, interactions of the two compounds with human serum albumin (HSA) and bovine serum albumin (BSA) were investigated by molecular modeling, density functional theory calculations (DFT) and multispectral techniques. The static quenching interaction deduced in the fluorescence quenching experiment is confirmed by the time-resolved analyses. The interactions of the two compounds with HSA/BSA induce molecular microenvironment and conformation changes, as assessed by synchronous and 3D fluorescence spectra, together with a destruction of polypeptide carbonyl hydrogen bond network by circular dichroism and Fourier transform infrared analyses. The thermodynamic analysis indicated that the spontaneous interaction was hydrogen bonding and hydrophobic forces. The binding constant Ka at 298 K was 3.54 × 105 M-1 in HSA-2,7-DBCB, 6.63 × 105 M-1 in HSA-3,6-DBCB, 1.32 × 105 M-1 in BSA-2,7-DBCB and 2.17 × 105 M-1 in BSA-3,6-DBCB. These results indicates that 3,6-DBCB binds HSA/BSA more strongly than 2,7-DBCB, which was estimated with DFT calculations. Site marker competition experiments coupled with molecular modeling studies confirmed that both compounds bind HSA/BSA at site I (subdomain IIA). The results suggest that interactions between 2,7-DBCB and 3,6-DBCB with HSA and BSA may affect the normal physiological activities in human and animals.


Assuntos
Carbazóis/química , Poluentes Ambientais/química , Modelos Moleculares , Soroalbumina Bovina/química , Animais , Dicroísmo Circular , Teoria da Densidade Funcional , Fluorescência , Humanos , Ligações de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Albumina Sérica , Termodinâmica
19.
Sensors (Basel) ; 19(13)2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31247893

RESUMO

Photon-counting analysis of nucleic acids plays a key role in many diagnostics applications for its accurate and non-invasive nature. However, conventional photon-counting instrumentations are bulky and expensive due to the use of conventional optics and a lack of optimization of electronics. In this paper, we present a portable, low-cost time-correlated single photon-counting (TCSPC) analysis system for DNA detection. Both optical and electronic subsystems are carefully designed to provide effective emission filtering and size reduction, delivering good DNA detection and fluorescence lifetime extraction performance. DNA detection has been verified by fluorescence lifetime measurements of a V-carbazole conjugated fluorophore lifetime bioassay. The time-to-digital module of the proposed TCSPC system achieves a full width at half maximum (FWHM) timing resolution from 121 to 145 ps and a differential non-linearity (DNL) between -8.5% and +9.7% of the least significant bit (LSB) within the 500 ns full-scale range (FSR). With a detection limit of 6.25 nM and a dynamic range of 6.8 ns, the proposed TCSPC system demonstrates the enabling technology for rapid, point-of-care DNA diagnostics.


Assuntos
Técnicas Biossensoriais , DNA/isolamento & purificação , Óptica e Fotônica , Carbazóis/química , DNA/química , Corantes Fluorescentes/química , Humanos
20.
Eur J Med Chem ; 178: 802-817, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31252285

RESUMO

We report in this work the discovery of novel allosteric MEK inhibitors by pharmacophore modeling and virtual screening. Two out of 13 virtual hit compounds were identified as MEK kinase inhibitors using a MEK1 binding assay. Structural derivations on the hit compound M100 (IC50 = 27.2 ±â€¯4.5 µM in RAF-MEK cascading assay) by substituent transformation and bioisosterism replacement have led to the synthesis of a small library of carbazoles. The enzymatic studies revealed the preliminary structure-activity relationships and the derivative 22k (IC50 = 12.8 ±â€¯0.5 µM) showed the most potent inhibitory effect against Raf-MEK cascading. Compound 7 was discovered as toxic as M100 to tumor cells whereas safer to HEK293 cells (IC50 > 100 µM) than M100 (IC50 = 8.9 ±â€¯2.0 µM). It suggests that carbazole is a good scaffold for the design of novel MEK inhibitors for therapeutic uses. More importantly, the developed pharmacophore model can serve as a reliable criterion in novel MEK inhibitor discovery.


Assuntos
Antineoplásicos/farmacologia , Carbazóis/farmacologia , Descoberta de Drogas , MAP Quinase Quinase Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Regulação Alostérica/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Carbazóis/síntese química , Carbazóis/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , MAP Quinase Quinase Quinases/metabolismo , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
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