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1.
J Med Chem ; 63(21): 12978-12991, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-33100009

RESUMO

Protein kinases C (PKCs) are a family of serine/threonine kinases involved in various cellular processes, including proliferation, differentiation, cell survival, and apoptosis. Here, we report the identification, structure-activity relationship (SAR), and 3D-QSAR studies of 69 natural indolocarbazoles, including 15 new compounds, from marine streptomyces strains. Interestingly, we found that the chair conformational isomer of 7-oxo-staurosporine (compound 15) inhibited PKCθ more potently than the corresponding boat isomer. An evaluation of kinase selectivity and antitumor efficacy revealed that 15 was a potent dual PKCθ/δ inhibitor and that it could efficiently inhibit tumor growth in pancreatic cancer (PC) by inducing cellular apoptosis and suppressing the NF-κB/p-P65 pathway. In addition, we demonstrated that overexpression of p-PKCδ and p-P65 was associated with poor survival rates in patients with PC, and p-PKCθ expression also showed significant positive correlations with p-PKCδ and p-P65 levels. Finally, the PC patient-derived xenograft model further confirmed the potential anti-PC efficacy of 15.


Assuntos
Carbazóis/química , Proteína Quinase C-delta/antagonistas & inibidores , Proteína Quinase C-theta/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Animais , Apoptose/efeitos dos fármacos , Sítios de Ligação , Carbazóis/metabolismo , Carbazóis/farmacologia , Carbazóis/uso terapêutico , Linhagem Celular Tumoral , Cristalografia por Raios X , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Proteína Quinase C-delta/metabolismo , Proteína Quinase C-theta/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Água do Mar/microbiologia , Transdução de Sinais/efeitos dos fármacos , Streptomyces/química , Streptomyces/metabolismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
2.
J Mol Graph Model ; 100: 107697, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32739642

RESUMO

Angiotensin-converting enzyme 2 (ACE2) is a membrane-bound zinc metallopeptidase that generates the vasodilatory peptide angiotensin 1-7 and thus performs a protective role in heart disease. It is considered an important therapeutic target in controlling the COVID-19 outbreak, since SARS-CoV-2 enters permissive cells via an ACE2-mediated mechanism. The present in silico study attempted to repurpose existing drugs for use as prospective viral-entry inhibitors targeting human ACE2. Initially, a clinically approved drug library of 7,173 ligands was screened against the receptor using molecular docking, followed by energy minimization and rescoring of docked ligands. Finally, potential binders were inspected to ensure molecules with different scaffolds were engaged in favorable contacts with both the metal cofactor and the critical residues lining the receptor's active site. The results of the calculations suggest that lividomycin, burixafor, quisinostat, fluprofylline, pemetrexed, spirofylline, edotecarin, and diniprofylline emerge as promising repositionable drug candidates for stabilizing the closed (substrate/inhibitor-bound) conformation of ACE2, thereby shifting the relative positions of the receptor's critical exterior residues recognized by SARS-CoV-2. This study is among the rare ones in the relevant scientific literature to search for potential ACE2 inhibitors. In practical terms, the drugs, unmodified as they are, may be introduced into the therapeutic armamentarium of the ongoing fight against COVID-19 now, or their scaffolds may serve as rich skeletons for designing novel ACE2 inhibitors in the near future.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/química , Antivirais/química , Betacoronavirus/química , Peptidil Dipeptidase A/química , Bibliotecas de Moléculas Pequenas/química , Motivos de Aminoácidos , Betacoronavirus/enzimologia , Carbazóis/química , Domínio Catalítico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Reposicionamento de Medicamentos , Difilina/análogos & derivados , Difilina/química , Interações Hospedeiro-Patógeno , Humanos , Ácidos Hidroxâmicos/química , Ligantes , Simulação de Acoplamento Molecular , Pandemias , Paromomicina/análogos & derivados , Paromomicina/química , Pemetrexede/química , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Relação Estrutura-Atividade , Termodinâmica
3.
J Med Chem ; 63(17): 9284-9299, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32787074

RESUMO

The development of new antimicrobial agents capable of curing drug-resistant bacteria-induced infections is becoming a major challenge to the global healthcare system. To develop antimicrobials with new molecular entities, a series of novel carbazole-based compounds were designed and synthesized by biomimicking the structural properties and biological function of antimicrobial peptides. Compound 29 was selected as a lead compound from the structure-activity relationship analyses and biological activity evaluation. Compound 29 showed excellent antimicrobial activity against Gram-positive bacteria (MICs = 0.78-1.56 µg/mL), poor hemolytic activity (HC50 > 200 µg/mL), and low cytotoxicity to mammalian cells. Compound 29 had fast bactericidal properties and effectively prevented bacterial resistance in laboratory simulations. Antibacterial mechanism studies revealed that compound 29 directly destroyed bacterial cell membranes, leading to bacterial deaths. Importantly, compound 29 displayed an excellent efficacy in a murine bacterial keratitis model caused by Staphylococcus aureus ATCC29213.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Carbazóis/química , Carbazóis/farmacologia , Desenho de Fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Interações Hidrofóbicas e Hidrofílicas , Animais , Bactérias Gram-Positivas/fisiologia , Cinética , Camundongos
4.
Sci Rep ; 10(1): 11767, 2020 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-32678219

RESUMO

Carbazole skeleton plays a significant role as a structural scaffold of many pharmacologically active compounds. Pyrazine-functionalized carbazole derivative was constructed by coupling 2-amino-5-bromo-3-methylaminepyrazine (ABMAP) into 3 and 6 positions of the carbazole ring. Multi-experimental methods were used, e.g., potentiometric, spectroscopic (ATR, UV, XRD powder,1H and13C NMR), electrochemical (cyclic voltammetry), and optical techniques, to receive the complete structural analysis, physicochemical (pKa, logP) and biological profile of a new carbazole derivative with acronym 3,6-PIRAMICAR. The interaction ability of the compound studied with potential cellular targets like Calf Thymus DNA (CT-DNA), or Bovine Serum Albumin (BSA) were also taken into account. Experiments showed the existence of strong binding, but no DNA or BSA cleavage was observed. The comparative analyzes of compounds anti-Candida action clearly show pH-dependent antifungal activity of 3,6-PIRAMICAR, which was strongly stimulated in the acidic media. Surprisingly, the titled compound turn out to be much more effective (14 times by MIC50; 8 times by MIC; c.a. 4 times by MFC) against Candida krusei than fluconazole at pH 4.


Assuntos
Antifúngicos/química , Antifúngicos/farmacologia , Carbazóis/química , Concentração de Íons de Hidrogênio , Luz , Pirazinas/química , Pirazinas/farmacologia , Citometria de Fluxo , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Análise Espectral , Relação Estrutura-Atividade
5.
Int J Mol Sci ; 21(11)2020 May 27.
Artigo em Inglês | MEDLINE | ID: covidwho-382045

RESUMO

Since the outbreak of the COVID-19 pandemic in December 2019 and its rapid spread worldwide, the scientific community has been under pressure to react and make progress in the development of an effective treatment against the virus responsible for the disease. Here, we implement an original virtual screening (VS) protocol for repositioning approved drugs in order to predict which of them could inhibit the main protease of the virus (M-pro), a key target for antiviral drugs given its essential role in the virus' replication. Two different libraries of approved drugs were docked against the structure of M-pro using Glide, FRED and AutoDock Vina, and only the equivalent high affinity binding modes predicted simultaneously by the three docking programs were considered to correspond to bioactive poses. In this way, we took advantage of the three sampling algorithms to generate hypothetic binding modes without relying on a single scoring function to rank the results. Seven possible SARS-CoV-2 M-pro inhibitors were predicted using this approach: Perampanel, Carprofen, Celecoxib, Alprazolam, Trovafloxacin, Sarafloxacin and ethyl biscoumacetate. Carprofen and Celecoxib have been selected by the COVID Moonshot initiative for in vitro testing; they show 3.97 and 11.90% M-pro inhibition at 50 µM, respectively.


Assuntos
Betacoronavirus/enzimologia , Inibidores de Proteases/química , Subtilisinas/antagonistas & inibidores , Proteínas Virais/antagonistas & inibidores , Antivirais/química , Antivirais/metabolismo , Sítios de Ligação , Carbazóis/química , Carbazóis/metabolismo , Celecoxib/química , Celecoxib/metabolismo , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Reposicionamento de Medicamentos , Humanos , Simulação de Acoplamento Molecular , Mutação de Sentido Incorreto , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Inibidores de Proteases/metabolismo , Estrutura Terciária de Proteína , Subtilisinas/genética , Subtilisinas/metabolismo , Proteínas Virais/genética , Proteínas Virais/metabolismo
6.
J Chromatogr A ; 1622: 461131, 2020 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-32381301

RESUMO

A carbazolic conjugated microporous polymer (designated as CZ-CMP) was successfully synthesized through Scholl reaction of carbazole with 1, 3, 5-triphenylbenzene. The CZ-CMP was characterized by FT-IR spectrum, X-ray diffraction, nitrogen sorption isotherms, and scanning electron microscopy. The characterization results showed that the CZ-CMP had a spherical structure with high surface area and good microporosity. Its adsorption performance was investigated by applying it as an adsorbent for the solid phase extraction (SPE) of phenyl urea herbicides (PUHs) (metoxuron, chlortoluron, isoproturon, monolinuron and buturon) from tea drinks samples prior to high performance liquid chromatographic detection. The CZ-CMP displayed high extraction efficiency for the PUHs, and the primary factors affecting the SPE efficiency including the type and volume of the eluent, sample solution pH, sample loading rate and sample volume were optimized. Under the optimized conditions, a good linear response for the analytes was observed in the range of 0.10-80.0 ng mL-1 with correlation coefficients (r) from 0.9937 to 0.9997. The limits of detection were measured to be in the range of 0.02-0.30 ng mL-1 and the limits of quantitation were in the range of 0.06-0.9 ng mL-1. The developed method was successfully applied for the determination of the five PUHs in four different kinds of drinks with the method recoveries between 83.7% and 118% and the relative standard deviations between 1.0% and 10%. Besides, the application potential of the CZ-CMP was evaluated by using it to extract different types of the organic compounds including some phthalate eaters (PAEs), chlorophenol (CPs), nitroimidazoles and polycyclic aromatic hydrocarbons (PAHs). The results indicated that the CZ-CMP had strong adsorption ability for the compounds with more hydrogen bonding sites and moderate hydrophobicity.


Assuntos
Herbicidas/isolamento & purificação , Compostos de Fenilureia/química , Polímeros/síntese química , Extração em Fase Sólida/métodos , Adsorção , Carbazóis/química , Cromatografia Líquida de Alta Pressão/métodos , Concentração de Íons de Hidrogênio , Compostos de Fenilureia/isolamento & purificação , Polímeros/química , Porosidade , Soluções , Espectroscopia de Infravermelho com Transformada de Fourier , Chá/química
7.
Alkaloids Chem Biol ; 84: 1-124, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32416951

RESUMO

The manzamine alkaloids are absolutely one of the most fascinating marine natural products. The representative manzamine alkaloids, manzamines A-C, were isolated from a marine sponge Haliclona sp. collected off Cape Manzamo, Okinawa, Japan. The manzamine alkaloids are a unique class of alkaloids possessing a characteristic heterocyclic system, and exhibit a diverse range of bioactivities including cytotoxicity, antimicrobial activity, antimalarial activity, antiviral and antiinflammatory activities, antiinsecticidal activity, and proteasome inhibitory activity. About 100 manzamine alkaloids have been isolated from more than 16 species of marine sponges belonging to 5 families. The unusual ring systems, an intriguing suggested biogenetic pathway, and promising biological activities of manzamine alkaloids have attracted great interest as challenging targets for the total synthesis. This review is the continuation of the previous review published in volume 60 of The Alkaloids and covers isolation, structure elucidation, biosynthesis and biogenesis, chemical synthesis, and biological activity of manzamine alkaloids reported from 2003 to 2018.


Assuntos
Alcaloides/farmacologia , Anti-Infecciosos/farmacologia , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Alcaloides/química , Alcaloides/metabolismo , Animais , Anti-Infecciosos/química , Anti-Infecciosos/metabolismo , Anti-Inflamatórios/química , Anti-Inflamatórios/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Carbazóis/química , Carbazóis/metabolismo , Carbazóis/farmacologia , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/metabolismo , Alcaloides Indólicos/farmacologia , Estrutura Molecular
8.
J Enzyme Inhib Med Chem ; 35(1): 1124-1136, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32366137

RESUMO

The human sirtuin silent information regulator 1 (SIRT1) is a NAD+-dependent deacetylase enzyme. It deacetylates many protein substrates, including histones and transcription factors, thereby controlling many physiological and pathological processes. Several synthetic inhibitors and activators of SIRT1 have been developed, and some therapeutic applications have been explored. The indole EX-527 and its derivatives are among the most potent and selective SIRT1 inhibitors. EX-527 has been often used as a pharmacological tool to explore the effect of SIRT1 inhibition in various cell types. Its therapeutic potential has, therefore, been evaluated in animal models for several pathologies, including cancer. It has also been tested in phase II clinical trial for the treatment of Huntington's disease (HD). In this review, we will provide an overview of the literature on EX-527, including its mechanism of inhibition and biological studies.


Assuntos
Carbazóis/farmacologia , Sirtuína 1/antagonistas & inibidores , Carbazóis/síntese química , Carbazóis/química , Linhagem Celular Tumoral , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Sirtuína 1/metabolismo , Relação Estrutura-Atividade
9.
Int J Mol Sci ; 21(11)2020 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-32471205

RESUMO

Since the outbreak of the COVID-19 pandemic in December 2019 and its rapid spread worldwide, the scientific community has been under pressure to react and make progress in the development of an effective treatment against the virus responsible for the disease. Here, we implement an original virtual screening (VS) protocol for repositioning approved drugs in order to predict which of them could inhibit the main protease of the virus (M-pro), a key target for antiviral drugs given its essential role in the virus' replication. Two different libraries of approved drugs were docked against the structure of M-pro using Glide, FRED and AutoDock Vina, and only the equivalent high affinity binding modes predicted simultaneously by the three docking programs were considered to correspond to bioactive poses. In this way, we took advantage of the three sampling algorithms to generate hypothetic binding modes without relying on a single scoring function to rank the results. Seven possible SARS-CoV-2 M-pro inhibitors were predicted using this approach: Perampanel, Carprofen, Celecoxib, Alprazolam, Trovafloxacin, Sarafloxacin and ethyl biscoumacetate. Carprofen and Celecoxib have been selected by the COVID Moonshot initiative for in vitro testing; they show 3.97 and 11.90% M-pro inhibition at 50 µM, respectively.


Assuntos
Betacoronavirus/enzimologia , Inibidores de Proteases/química , Subtilisinas/antagonistas & inibidores , Proteínas Virais/antagonistas & inibidores , Antivirais/química , Antivirais/metabolismo , Sítios de Ligação , Carbazóis/química , Carbazóis/metabolismo , Celecoxib/química , Celecoxib/metabolismo , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Reposicionamento de Medicamentos , Humanos , Simulação de Acoplamento Molecular , Mutação de Sentido Incorreto , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Inibidores de Proteases/metabolismo , Estrutura Terciária de Proteína , Subtilisinas/genética , Subtilisinas/metabolismo , Proteínas Virais/genética , Proteínas Virais/metabolismo
10.
Chem Biol Interact ; 323: 109077, 2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32246921

RESUMO

7H-Dibenzo[c,g]carbazole (DBC), a local and systemic carcinogen in animal studies, is a common environmental pollutant. It generally co-occurs in a variety of organic complex mixtures derived from incomplete combustion of organic matter. Despite high lipophilicity, DBC is more water-soluble and faster metabolized than the homocyclic aromatics. Moreover, greater polarity, high bioaccumulation potential, and persistence in the environment may imply DBC's higher biological significance and impact on human health, even at lower concentrations. The biotransformation pathways of DBC are incompletely known and the ultimate carcinogenic metabolite(s) are not clearly identified as yet. Structure-biological studies suggest two ways of activation: at the ring carbon atoms and at the pyrrole nitrogen. It is supposed that the particular pathway of biotransformation might be connected with the tissue/organ specificity of DBC. Cytochrome P450 (CYP) family of enzymes plays a pivotal role in the metabolism of DBC; though, the one-electron activation and the aldo-keto reductase-catalyzed oxidation are also involved in metabolic activation. Additionally, DBC can be photoactivated even at physiologically relevant doses of UVA light due to the extended aromatic ring system resulting in strong genotoxicity and oxidative stress. The goal of this review is to summarize current knowledge on mechanisms of DBC activation and possible implications for toxicity, genotoxicity, and carcinogenicity.


Assuntos
Carbazóis/toxicidade , Redes e Vias Metabólicas/efeitos dos fármacos , Animais , Carbazóis/química , Carbazóis/metabolismo , Carcinogênese/induzido quimicamente , Carcinogênese/efeitos dos fármacos , Humanos , Luz , Oxirredução , Relação Estrutura-Atividade
11.
Talanta ; 214: 120842, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32278426

RESUMO

Hypochlorite (ClO-) could be used as a diagnostic marker for inflammation and related diseases. Although there have been many reports on probes for ClO- imaging, there was still a lack of specificity and anti-interference ability. Herein, carbazole (NEC) and tetraphenylethylene (TPE) equipped with thiobarbituric acid (TBA), NEC-TBA and TPE-TBA, were synthesized and used as a fluorescence biosensor for monitoring ClO- with aggregation-induced emission (AIE) effect. we identified that TPE-TBA, with formed nanoparticles in the mean grain size at 76 nm (5 µM), was a superior probe to target ClO- over other analytes with fluorescence "turn off" strategy. Subsequently, to explore the bioimaging application, TPE-TBA was able to sense exogenous ClO- in living HeLa cells through fluorescence imaging. In zebrafish model, TPE-TBA effectively captured exogenous ClO- in the entire organization of zebrafish. Overall, these AIE-based probes merit further development as organism targeting ClO- sensors.


Assuntos
Corantes Fluorescentes/química , Ácido Hipocloroso/análise , Nanopartículas/química , Imagem Óptica , Animais , Técnicas Biossensoriais , Carbazóis/química , Corantes Fluorescentes/síntese química , Células HeLa , Humanos , Estrutura Molecular , Tamanho da Partícula , Espectrometria de Fluorescência , Estilbenos/química , Propriedades de Superfície , Tiobarbitúricos/química , Células Tumorais Cultivadas , Peixe-Zebra
12.
Chem Commun (Camb) ; 56(36): 4910-4913, 2020 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-32238998

RESUMO

A simple di(thioamido)carbazole 1 serves as a potent multispecific transporter for various biologically relevant oxyanions, such as drugs, metabolites and model organic phosphate. The transport kinetics of a wide range of oxyanions can be easily quantified by a modified lucigenin assay in both large and giant unilamellar vesicles.


Assuntos
Carbazóis/metabolismo , Bicamadas Lipídicas/metabolismo , Oxigênio/metabolismo , Tioamidas/metabolismo , Lipossomas Unilamelares/metabolismo , Transporte Biológico , Carbazóis/química , Cinética , Bicamadas Lipídicas/química , Estrutura Molecular , Oxigênio/química , Tioamidas/química , Lipossomas Unilamelares/química
13.
Chem Pharm Bull (Tokyo) ; 68(4): 326-331, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32238650

RESUMO

Oiling-out is a unique phenomenon that the liquid phase is separated into two parts during crystallization. The emergence of new liquid phase changes the environment where crystals nucleate and grow, we call "mother phase," because target material and impurities become distributed to each phase according to their own particular distribution ratios. In our previous study on crystallization of an intermediate compound with impurities (denoted Imp-A, -B, and -C), we found that when oiling-out was formed, incorporation of Imp-C was inhibited, because Imp-C was distributed to the mother phase less than Imp-A and -B. In this study, we explored the effect of EtOH solution composition on impurity profile of the crystallized product in oiling-out crystallization, and found that the low content of Imp-B in the EtOH solution, the higher content of Imp-C in the crystallized product. Our finding revealed that not only oiling-out but also Imp-B played a key role in inhibiting the incorporation of Imp-C into the crystals.


Assuntos
Carbazóis/química , Etanol/química , Piperidinas/química , Cristalização , Estrutura Molecular , Tamanho da Partícula , Soluções , Propriedades de Superfície
14.
Eur J Med Chem ; 191: 112181, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32113125

RESUMO

Here, we formulated and investigated the structure-activity relationships of novel N-substituted carbazole sulfonamide derivatives with improved physicochemical properties. Most of these new compounds displayed good aqueous solubility. Certain molecules presented strong in vitro antiproliferative and in vivo antitumor activity. Relative to the control, 50 mg/kg compound 3v substantially reduced human HepG2 xenograft mouse tumor growth by 54.5% and its efficacy was comparable to that of CA-4P. Compound 3h demonstrated anticancer efficacy in both subcutaneous and orthotopic HepG2 xenograft mouse models. We also developed a novel synthetic method for 7-hydroxy-substituted carbazole sulfonamides. Compared with the control, 25 mg/kg compound 4c inhibited human HepG2 xenograft mouse tumor growth by 71.7% and was more potent than 50 mg/kg CA-4P with only 50% tumor shrinkage efficacy. Among the three water-soluble carbazole sulfonamide derivatives formulated in the present study, compound 4c displayed the most effective tumor growth inhibition in vivo and merit further investigation as potential antitumor agents for cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Carbazóis/farmacologia , Sulfonamidas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Carbazóis/síntese química , Carbazóis/química , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Ratos , Solubilidade , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Células Tumorais Cultivadas , Água/química
15.
Chem Biodivers ; 17(5): e1900550, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32149467

RESUMO

Two series of carbazole analogs of 8-methoxy-N-substituted-9H-carbazole-3-carboxamides (series 1) and carbazolyl substituted rhodanines (series 2) were synthesized through facile synthetic routes. All the final compounds from these two series were evaluated for their preliminary in vitro antifungal and antibacterial activity against four fungal (Candida albicans, Cryptococcus neoformans, Cryptococcus tropicalis and Aspergillus niger) and four bacterial (Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa) strains, respectively. Among the tested compounds, three compounds of series 1 displayed promising antifungal and antibacterial activity, especially against C. neoformans and S. aureus. In addition, one compound of series 1 displayed notable antimicrobial activity (MIC: 6.25 µg/mL) against clinical isolates of C. albicans and C. neoformans (MIC: 12.5 µg/mL). From the second series, four compounds exhibited significant antifungal and antibacterial activity, especially against C. neoformans and S. aureus. The most active compound of series 2 displayed a prominent antimicrobial activity against C. neoformans (MIC: 3.125 µg/mL) and S. aureus (MIC: 1.56 µg/mL), respectively.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Carbazóis/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Aspergillus niger/efeitos dos fármacos , Bacillus subtilis/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Carbazóis/síntese química , Carbazóis/química , Cryptococcus/efeitos dos fármacos , Relação Dose-Resposta a Droga , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade
16.
Philos Trans A Math Phys Eng Sci ; 378(2167): 20190450, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32008445

RESUMO

Here, a bioinspired strategy is used to prepare well-ordered nanotubular structures, as observed in animals and plants, such as gecko toe pads or corals. The nanotubes are obtained by templateless electropolymerization of thieno[3,4-b]thiophene-based monomers with various aromatic groups in an organic solvent (dichloromethane). The most interesting and robust structures were obtained with carbazole and pyrene substituents to the base monomer structure, since these groups participate significantly in the polymerization and also have strong π-stacking interactions. The addition of water to electropolymerization solvent significantly impacted the formation of nanotubes, as it caused the release of a significant amount of H2 and O2 bubbles, depending on the electropolymerization method. Identifying templateless approaches to vary nanotubular structures is very interesting, as these materials are sought-after for applications in water harvesting systems. This article is part of the theme issue 'Bioinspired materials and surfaces for green science and technology (part 3)'.


Assuntos
Eletroquímica/métodos , Cloreto de Metila/química , Nanotecnologia/métodos , Nanotubos/química , Tiofenos/química , Biomimética , Carbazóis/química , Química Verde , Hidrogênio/química , Substâncias Macromoleculares , Microscopia Eletrônica de Varredura , Compostos Orgânicos , Oxigênio/química , Polímeros/química , Solventes/química , Propriedades de Superfície , Água/química , Molhabilidade
17.
Chem Pharm Bull (Tokyo) ; 68(2): 167-172, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32009084

RESUMO

A heterogeneous metal catalyst enabled the intramolecular oxidative coupling of diarylamines to form carbazoles with molecular oxygen as the sole oxidant. Rh/C had efficient catalytic activity and allowed the catalyst loading to be reduced to 0.1 mol% while maintaining excellent yields of carbazoles. This reaction is operationally simple in an open-to-air setup, and provides a green and atom-economical process for an efficient synthetic approach to N-substituted carbazoles.


Assuntos
Carbazóis/síntese química , Carbazóis/química , Catálise , Técnicas de Química Sintética , Acoplamento Oxidativo , Oxigênio/química , Ródio/química
18.
Biomed Res Int ; 2020: 7821913, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32104704

RESUMO

Murraya koenigii is a well-known Indian medicinal herb, and a carbazole alkaloid (mahanine) from this plant causes apoptosis in cancer cells. Here, we investigated how seasonal and geographical variations influence carbazole alkaloids composition and medicinal property of this plant against cancer cells in vitro and in vivo. Leaflets were collected from various places in different seasons for three years. A mahanine-enriched fraction (MEF) was prepared in two steps using ethanol and water. The best plant was selected based on the highest percent of mahanine. MEF prepared from leaflets of nine different locations showed a different concentration of identified markers (mahanine, mahanimbine, and koenimbine) which exhibited differential reduced metabolic activity against ovarian cancer, mahanine being the best. Our systematic study revealed that mahanine content was highest during September-December. Interestingly, MEF from southern part (tropical zone) exhibited 43 ± 2.5% mahanine compared to 2.7 ± 1.3% in northeastern part (subtropical zone) with five folds higher activity against PA1. Moreover, MEF reduced metabolic activity of sixteen cancer cell lines from nine different origins and significantly reduced tumor mass in lung and ovarian cancer xenograft models. Taken together, this is the first report demonstrating the marker's content in these leaflets is highly dependent on location/season. A positive correlation between biological activity and mahanine concentration was established in MEF. Such a comprehensive study suggests that the selection of location and suitable season for collection of any plant materials with biologically active stable markers in sufficient quantity play a decisive role in determining the fate of their medicinal property.


Assuntos
Alcaloides , Antineoplásicos Fitogênicos , Carbazóis , Murraya , Neoplasias Experimentais/tratamento farmacológico , Estações do Ano , Células A549 , Alcaloides/química , Alcaloides/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Carbazóis/química , Carbazóis/farmacologia , Feminino , Células HCT116 , Células HeLa , Humanos , Camundongos , Camundongos Nus , Murraya/química , Murraya/crescimento & desenvolvimento , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Macromol Rapid Commun ; 41(8): e2000004, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32100902

RESUMO

Chemiluminescence (CL) has recently been featured as a new external light source for various photoinduced reactions with attractive features such as eliminating continuous energy supply and advanced light source setups. In the present study, the free-radical-promoted cationic polymerization of cyclohexene oxide, n-butyl vinyl ether, and N-vinyl carbazole under CL irradiation is described. The method is based on the visible-light-induced generation of electron donor radicals from bis-(4-methoxybenzoyl)diethyl germane (BAG), bis(2,4,6-trimethylbenzoyl) phenyl phosphinate, and camphorquinone by CL illumination followed by electron transfer to diphenyl iodonium hexafluorophosphate (Ph2 I+ PF6 - ) to form corresponding cations capable of initiating cationic polymerization. The applicability of the process to network formation is also demonstrated by using a bifunctional monomer, tri(ethylene glycol) divinyl ether.


Assuntos
Carbazóis/química , Cicloexenos/química , Éteres/química , Luminescência , Compostos de Vinila/química , Cátions/síntese química , Cátions/química , Radicais Livres/química , Luz , Estrutura Molecular , Polimerização
20.
Nat Chem Biol ; 16(4): 383-386, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32066966

RESUMO

Cycloaddition reactions generate chemical complexity in a single step. Here we report the crystal structures of three homologous plant-derived cyclases involved in the biosynthesis of iboga and aspidosperma alkaloids. These enzymes act on the same substrate, named angryline, to generate three distinct scaffolds. Mutational analysis reveals how these highly similar enzymes control regio- and stereo-selectivity.


Assuntos
Alcaloides/biossíntese , Aspidosperma/química , Tabernaemontana/química , Alcaloides/química , Carbazóis/química , Reação de Cicloadição/métodos , Alcaloides Indólicos/química , Plantas/química
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