Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.387
Filtrar
1.
Anticancer Res ; 40(12): 6907-6914, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33288584

RESUMO

BACKGROUND/AIM: Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. Resistance to chemotherapy and side-effects remain a challenge for treating advanced and recurrent HCC. Therefore, there is an emerging need to develop new drugs to treat HCC. MATERIALS AND METHODS: We evaluated the anti-growth activity of flavopereirine in HepG2 and Huh7 HCC cell lines. Cell viability, cell-cycle profile, apoptosis, and autophagy-related protein expressions were analysed after flavopereirine treatment. RESULTS: Flavopereirine treatment induced G0/G1 cell-cycle arrest, with an increase of sub-G1 cells detected at the higher concentration and longer exposure to flavopereirine in HCC cells. Intrinsic and extrinsic pathways were involved in flavopereirine-induced apoptosis, as demonstrated by an increase of cleaved caspase 8 and 9 by western blotting. An alteration of autophagy-related protein expression was also found after flavopereirine treatment. CONCLUSION: Taken together, the current results indicate that flavopereirine exhibits good anticancer activity in HCC cells.


Assuntos
Antineoplásicos/farmacologia , Proteínas Relacionadas à Autofagia/genética , Carbolinas/farmacologia , Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hepáticas/genética , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/metabolismo
2.
Chem Biol Interact ; 330: 109229, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32835667

RESUMO

Cell cycle dysregulation is the mainstay of aberrant cell proliferation, which leads to tumor progression. Mutations in tumor cells initiate various dysregulated pathways and spontaneous over-proliferation with genomic/chromosomal instability. Despite advances in cancer therapy, it has remained a medicinal challenge to treat. Besides, the complexity of pathophysiological pathways behind cancer raises the need for novel multi-target agents, possessing fewer side effects. Alkaloid-based therapies have been explored so far to target cell division in cancer, including vinca alkaloids. As a class of hopeful ß-carboline derivatives, growing evidence has indicated their auspicious roles in combating cancer by inhibiting topoisomerase (TOPO), kinesin Eg5, telomerase, cyclin-dependent kinase (CDK), IκB kinase (IKK), and polo-like kinase-1 (PLK1) in the transition phases of cell cycle. In this review, in vitro potential of ß-carboline has been revealed through targeting cell division cycle at different phases. In conclusion, ß-carboline alkaloids could be introduced as novel candidates in cancer therapy.


Assuntos
Carbolinas/farmacologia , Ciclo Celular/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Carbolinas/uso terapêutico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Humanos
3.
J Med Chem ; 63(17): 9623-9649, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32787097

RESUMO

The rise of multidrug resistant (MDR) Gram-negative (GN) pathogens and the decline of available antibiotics that can effectively treat these severe infections are a major threat to modern medicine. Developing novel antibiotics against MDR GN pathogens is particularly difficult as compounds have to permeate the GN double membrane, which has very different physicochemical properties, and have to circumvent a plethora of resistance mechanisms such as multiple efflux pumps and target modifications. The bacterial type II topoisomerases DNA gyrase (GyrA2B2) and Topoisomerase IV (ParC2E2) are highly conserved targets across all bacterial species and validated in the clinic by the fluoroquinolones. Dual inhibitors targeting the ATPase domains (GyrB/ParE) of type II topoisomerases can overcome target-based fluoroquinolone resistance. However, few ATPase inhibitors are active against GN pathogens. In this study, we demonstrated a successful strategy to convert a 2-carboxamide substituted azaindole chemical scaffold with only Gram-positive (GP) activity into a novel series with also potent activity against a range of MDR GN pathogens. By systematically fine-tuning the many physicochemical properties, we identified lead compounds such as 17r with a balanced profile showing potent GN activity, high aqueous solubility, and desirable PK features. Moreover, we showed the bactericidal efficacy of 17r using a neutropenic mouse thigh infection model.


Assuntos
Carbolinas/química , Carbolinas/farmacologia , DNA Girase/metabolismo , DNA Topoisomerase IV/metabolismo , Desenho de Fármacos , Escherichia coli/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Animais , DNA Girase/química , DNA Topoisomerase IV/química , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Escherichia coli/enzimologia , Camundongos , Modelos Moleculares , Conformação Proteica , Staphylococcus aureus/enzimologia
4.
J Med Chem ; 63(17): 9672-9694, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32787109

RESUMO

Transient receptor potential melastatin 8 (TRPM8) ion channel represents a valuable pharmacological option for several therapeutic areas. Here, a series of conformationally restricted derivatives of the previously described TRPM8 antagonist N,N'-dibenzyl tryptophan 4 were prepared and characterized in vitro by Ca2+-imaging and patch-clamp electrophysiology assays. Molecular modeling studies led to identification of a broad and well-defined interaction network of these derivatives inside the TRPM8 binding site, underlying their antagonist activity. The (5R,11aS)-5-(4-chlorophenyl)-2-(4-fluorobenzyl)-5,6,11,11a-tetrahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indole-1,3(2H)-dione (31a) emerged as a potent (IC50 = 4.10 ± 1.2 nM), selective, and metabolically stable TRPM8 antagonist. In vivo, 31a showed significant target coverage in an icilin-induced WDS (at 11.5 mg/kg ip), an oxaliplatin-induced cold allodynia (at 10-30 µg sc), and CCI-induced thermal hyperalgesia (at 11.5 mg/kg ip) mice models. These results confirm the tryptophan moiety as a solid pharmacophore template for the design of highly potent modulators of TRPM8-mediated activities.


Assuntos
Analgésicos/química , Analgésicos/farmacologia , Carbolinas/química , Carbolinas/farmacologia , Canais de Cátion TRPM/agonistas , Canais de Cátion TRPM/metabolismo , Analgésicos/metabolismo , Analgésicos/uso terapêutico , Animais , Sítios de Ligação , Carbolinas/metabolismo , Carbolinas/uso terapêutico , Simulação de Acoplamento Molecular , Neuralgia/tratamento farmacológico , Conformação Proteica , Ratos , Canais de Cátion TRPM/química
5.
Nat Immunol ; 21(7): 727-735, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32541831

RESUMO

Stimulator-of-interferon genes (STING) is vital for sensing cytosolic DNA and initiating innate immune responses against microbial infection and tumors. Redox homeostasis is the balance of oxidative and reducing reactions present in all living systems. Yet, how the intracellular redox state controls STING activation is unclear. Here, we show that cellular redox homeostasis maintained by glutathione peroxidase 4 (GPX4) is required for STING activation. GPX4 deficiency enhanced cellular lipid peroxidation and thus specifically inhibited the cGAS-STING pathway. Concordantly, GPX4 deficiency inhibited herpes simplex virus-1 (HSV-1)-induced innate antiviral immune responses and promoted HSV-1 replication in vivo. Mechanistically, GPX4 inactivation increased production of lipid peroxidation, which led to STING carbonylation at C88 and inhibited its trafficking from the endoplasmic reticulum (ER) to the Golgi complex. Thus, cellular stress-induced lipid peroxidation specifically attenuates the STING DNA-sensing pathway, suggesting that GPX4 facilitates STING activation by maintaining redox homeostasis of lipids.


Assuntos
Herpes Simples/imunologia , Proteínas de Membrana/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Animais , Carbolinas/farmacologia , Células Cultivadas , DNA Viral/imunologia , Modelos Animais de Doenças , Retículo Endoplasmático/metabolismo , Feminino , Fibroblastos , Complexo de Golgi/metabolismo , Células HEK293 , Herpes Simples/virologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/imunologia , Homeostase/imunologia , Humanos , Imunidade Inata , Peroxidação de Lipídeos/genética , Peroxidação de Lipídeos/imunologia , Macrófagos Peritoneais/citologia , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Proteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , Nucleotidiltransferases/metabolismo , Oxirredução , Oximas/farmacologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/antagonistas & inibidores , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Cultura Primária de Células , Carbonilação Proteica/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Sulfonamidas/farmacologia , Células THP-1 , Replicação Viral/imunologia
6.
Sci Rep ; 10(1): 10230, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32576869

RESUMO

Actinomycetes bacteria produce diverse bioactive molecules that are useful as drug seeds. To improve their yield, researchers often optimize the fermentation medium. However, exactly how the extracellular chemicals present in the medium activate secondary metabolite gene clusters remains unresolved. BR-1, a ß-carboline compound, was recently identified as a chemical signal that enhanced reveromycin A production in Streptomyces sp. SN-593. Here we show that BR-1 specifically bound to the transcriptional regulator protein RevU in the reveromycin A biosynthetic gene cluster, and enhanced RevU binding to its promoter. RevU belongs to the LuxR family regulator that is widely found in bacteria. Interestingly, BR-1 and its derivatives also enhanced the production of secondary metabolites in other Streptomyces species. Although LuxR-N-acyl homoserine lactone systems have been characterized in Gram-negative bacteria, we revealed LuxR-ß-carboline system in Streptomyces sp. SN-593 for the production of secondary metabolites. This study might aid in understanding hidden chemical communication by ß-carbolines.


Assuntos
Proteínas de Bactérias/metabolismo , Carbolinas/farmacologia , Regulação Bacteriana da Expressão Gênica , Piranos/metabolismo , Proteínas Repressoras/metabolismo , Compostos de Espiro/metabolismo , Streptomyces/metabolismo , Transativadores/metabolismo , Proteínas de Bactérias/genética , Perfilação da Expressão Gênica , Metaboloma/efeitos dos fármacos , Família Multigênica , Regiões Promotoras Genéticas , Proteínas Repressoras/genética , Streptomyces/classificação , Streptomyces/efeitos dos fármacos , Streptomyces/genética , Transativadores/genética
7.
Artigo em Inglês | MEDLINE | ID: mdl-32278957

RESUMO

Norharmane is an indole alkaloid that can be found in several terrestrial plants, as well as in some dinoflagellates and cyanobacteria. The aim of this study was to focus on the way this metabolite impacts the plant metabolism of the model species Arabidopsis thaliana. This metabolite caused increase of secondary and adventitious roots, as well as torsion, toxic effects, and a decrease in root length. Moreover, norharmane altered the cellular arrangement, resulting in unfinished cell walls, decreased auxin content and inhibited PIN proteins activity. All the alterations suggest that norharmane alters polar auxin transport by inhibiting PIN2, PIN3 and PIN7 transport proteins, thus causing a significant inhibitory effect on the growth of A. thaliana seedlings.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Carbolinas , Regulação da Expressão Gênica de Plantas , Raízes de Plantas , Arabidopsis/efeitos dos fármacos , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Transporte Biológico/efeitos dos fármacos , Carbolinas/farmacologia , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Raízes de Plantas/efeitos dos fármacos
8.
Molecules ; 25(7)2020 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-32244444

RESUMO

Use of a Pictet-Spengler reaction of tryptamine and l-tryptophan methyl ester and subsequent reduction of the nitro group followed by further cyclocondensation with aryl aldehydes and formyl-substituted carboxylic acids, including ferrocene-based components, furnished a series of diastereomeric 6-aryl-substituted 5,6,8,9,14,14b-hexahydroindolo[2',3':3,4]pyrido[1-c]-quinazolines and 5,5b,17,18-tetrahydroindolo[2',3':3,4]pyrido[1,2-c]isoindolo[2,1-a]quinazolin-11-(15bH)-ones with the elements of central-, planar and conformational chirality. The relative configuration and the conformations of the novel polycyclic indole derivatives were determined by 1H- and 13C-NMR methods supplemented by comparative DFT analysis of the possible diastereomers. The structure of one of the pentacyclic methyl esters with defined absolute configuration "S" was also confirmed by single crystal X-ray diffraction measurement. Accounting for the characteristic substituent-dependent diastereoselective formation of the products multistep mechanisms were proposed on the basis of the results of DFT modeling. Preliminary in vitro cytotoxic assays of the products revealed moderate-to-significant antiproliferative effects against PANC-1-, COLO-205-, A-2058 and EBC-1 cell lines that proved to be highly dependent on the stereostructure and on the substitution pattern of the pending aryl substituent.


Assuntos
Carbolinas/química , Compostos Ferrosos/química , Metalocenos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Carbolinas/síntese química , Carbolinas/farmacologia , Linhagem Celular Tumoral , Técnicas de Química Sintética , Teoria da Densidade Funcional , Compostos Ferrosos/síntese química , Compostos Ferrosos/farmacologia , Humanos , Metalocenos/síntese química , Metalocenos/farmacologia , Modelos Teóricos , Conformação Molecular , Estrutura Molecular , Análise Espectral , Relação Estrutura-Atividade
9.
Molecules ; 25(5)2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32155800

RESUMO

The increasing resistance of rice sheath blight caused by Rhizoctonia solani highlights the need for highly effective and environmentally benign agents. Natural ß-carboline alkaloids were simplified to obtain a series of indole derivatives, and their fungicidal activity and preliminary mode of action against R. solani were also evaluated. The initial hit indole (7) displayed significant fungicidal activity with an EC50 value of 25.56 µg/mL, and was selected for further optimization. Importantly, compound 55, the most active compound, had an EC50 value of 0.62 µg/mL, and approximately 300-fold more potent than validamycin A (EC50 = 183.00 µg/mL). In vivo bioassay also demonstrated that compound 55 showed better fungicidal activities than validamycin A. Moreover, the mechanism studies revealed that compound 55 not only caused remarkable morphological and structural alterations of R. solani hyphae, but also induced the loss of mitochondrial membrane potential and interfered with DNA synthesis. Therefore, compound 55 showed superior fungicidal activity against R. solani, and the elucidated mode of action supported the potential application of compound 55 against rice sheath blight.


Assuntos
Alcaloides/química , Alcaloides/farmacologia , Carbolinas/química , Carbolinas/farmacologia , Fungicidas Industriais/química , Indóis/química , Permeabilidade da Membrana Celular/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estrutura Molecular , Fenótipo , Doenças das Plantas/microbiologia , Espécies Reativas de Oxigênio/metabolismo , Rhizoctonia/efeitos dos fármacos , Rhizoctonia/metabolismo , Rhizoctonia/ultraestrutura , Relação Estrutura-Atividade
10.
Int J Nanomedicine ; 15: 465-481, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021191

RESUMO

Background: 1-(4-isopropylphenyl)-ß-carboline-3-carboxylic acid (ICCA) was modified by Trp-Phe-Phe to form 1-(4-isopropylphenyl)-ß-carboline-3-carbonyl-Trp-Phe-Phe (ICCA-WFF). Purpose: The object of preparing ICCA-WFF was to enhance the in vivo efficacy of ICCA, to explore the possible targeting action, and to visualize the nano-feature. Methods: The advantages of ICCA-WFF over ICCA were demonstrated by a series of in vivo assays, such as anti-tumor assay, anti-arterial thrombosis assay, anti-venous thrombosis assay, P-selectin expression assay, and GPIIb/IIIa expression assay. The nano-features of ICCA-WFF were visualized by TEM, SEM and AFM images. The thrombus targeting and tumor-targeting actions were evidenced by FT-MS spectrum analysis. Results: The minimal effective dose of ICCA-WFF slowing tumor growth and inhibiting thrombosis was 10-fold lower than that of ICCA. ICCA-WFF, but not ICCA, formed nano-particles capable of safe delivery in blood circulation. In vivo ICCA-WFF, but not ICCA, can target thrombus and tumor. In thrombus and tumor, ICCA-WFF released Trp-Phe-Phe and/or ICCA. Conclusion: Modifying ICCA with Trp-Phe-Phe successfully enhanced the anti-tumor activity, improved the anti-thrombotic action, formed nano-particles, targeted tumor tissue and thrombus, and provided an oligopeptide modification strategy for heterocyclic compounds.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Carbolinas/química , Carbolinas/farmacologia , Fibrinolíticos/farmacologia , Peptídeos/química , Animais , Domínio Catalítico , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Fibrinolíticos/química , Humanos , Masculino , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Nanopartículas/química , Selectina-P/química , Selectina-P/metabolismo , Peptídeos/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Ratos Sprague-Dawley , Trombose/sangue , Trombose/tratamento farmacológico
11.
Cancer Immunol Immunother ; 69(5): 813-824, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32055920

RESUMO

Despite significant therapeutic improvements chronic lymphocytic leukemia (CLL) remains an incurable disease and there is a persistent pursuit of new treatment alternatives. Lurbinectedin, a selective inhibitor of active transcription of protein-coding genes, is currently in phase II/III clinical trials for solid tumors such as small-cell lung cancer (SCLC). In this study, we aimed to evaluate the activity of Lurbinectedin on circulating mononuclear cells from CLL patients and to determine whether Lurbinectedin could affect the cross-talk between B-CLL cells and the tumor microenvironment. We found that Lurbinectedin induced a dose- and time-dependent death in all cell types evaluated, with B cells, monocytes and monocytic myeloid derived suppressor cells (Mo-MDSC) being the most susceptible populations. At sub-apoptotic doses, Lurbinectedin decreased the expression of CCR7 in B-CLL cells and impaired their migration towards CCL19 and CCL21. Furthermore, low concentrations of Lurbinectedin stimulated the synthesis of pro-IL1ß in monocytes and nurse-like cells, without inducing the inflammasome activation. Altogether, these results indicate that Lurbinectedin might have antitumor activity in CLL due to its direct action on leukemic cells in combination with its effects on the tumor microenvironment. Our findings encourage further investigation of Lurbinectedin as a potential therapy for CLL.


Assuntos
Carbolinas/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Quimiocina CCL19/imunologia , Quimiocina CCL19/metabolismo , Quimiocina CCL21/imunologia , Quimiocina CCL21/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/patologia , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/metabolismo , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Cultura Primária de Células , Receptores CCR7/imunologia , Receptores CCR7/metabolismo , Células Tumorais Cultivadas , Microambiente Tumoral/imunologia
12.
Eur J Med Chem ; 187: 111935, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31816556

RESUMO

A series of methyl ß-carboline carboxylates (2a-g) and of imide-ß-carboline derivatives containing the phthalimide (4a-g), maleimide (5b, g) and succinimide (6b, e, g) moiety were synthesized, and evaluated for their activity against Mycobacterium tuberculosis H37Rv. The most active ß-carboline derivatives against the reference strain were assayed for their cytotoxicity and the activity against resistant M. tuberculosis clinical isolates. Farther, structure-activity relationship (SAR) studies were carried out using the three and four-dimensional approaches for starting to understand the way of ß-carboline activity in M. tuberculosis. All 19 ß-carboline derivatives were assayed, firstly, by determining the minimum inhibitory concentration (MIC) using resazurin microtiter assay plate (REMA) in M. tuberculosis H37Rv. Then, five derivatives (2c, 4a, 4e, 4g, 6g), which showed MIC ≤ 125 µg/mL, were assayed in nine resistant M. tuberculosis clinical isolates (five MDR, three isoniazid monoresistant and one isoniazid plus streptomycin resistant). The MIC values against the resistant clinical isolates ranged from 31.25 to >250 µg/mL. All five derivatives were non-cytotoxic to the VERO cell line, determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, at the tested concentration (selectivity index ranged from <1.74 to 14.4). Our study demonstrated that (2c) and (6g) derivatives had better anti-M. tuberculosis activity, especially against resistant clinical isolates, what makes them scaffold candidates for further investigations about their anti-tuberculosis activity. The SAR study conducted with the 19 ß-carboline derivatives showed the importance of steric effects for the synthesized ß-carbolines against M tuberculosis, and these models can be used for future proposition of new derivatives, increasing the chances of obtaining potentially anti-tuberculosis compounds.


Assuntos
Antituberculosos/farmacologia , Carbolinas/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Animais , Antituberculosos/síntese química , Antituberculosos/química , Carbolinas/síntese química , Carbolinas/química , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade , Células Vero
13.
Nat Prod Res ; 34(4): 489-493, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30369253

RESUMO

(±)-Quassidine K (1), a pair of new bis-ß-carboline alkaloid enantiomers, were isolated from Picrasma quassioides. Their structures were determined on the basis of detailed spectroscopic data analysis. The absolute configurations of (+)-S-quassidine K (1a) and (-)-R-quassidine K (1b) were determined by comparing with the reported experimental ECD spectra after chiral separation. The cytotoxicity assay showed activity against HeLa cells with IC50 values of 15.8 and 20.1 µM, respectively.


Assuntos
Alcaloides/isolamento & purificação , Antineoplásicos/isolamento & purificação , Carbolinas/isolamento & purificação , Picrasma/química , Alcaloides/química , Alcaloides/farmacologia , Antineoplásicos/farmacologia , Carbolinas/química , Carbolinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Estereoisomerismo
14.
PLoS One ; 14(12): e0227278, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31887216

RESUMO

The iron dependent, programmed cell death, ferroptosis was described first in tumour cells. It showed distinct features from the already known cell death forms such as apoptosis, necrosis and autophagy. The caspase independent cell death could be induced by the depletion of glutathione by erastin or by the inhibition of the lipid peroxide scavenger enzyme GPX4 by RSL3 and it was accompanied by the generation of lipid reactive oxygen species. Recently, ferroptosis-like cell death associated to glutathione depletion, lipid peroxidation and iron dependency could also be induced in plant cells by heat treatment. Unfortunately, the mediators and elements of the ferroptotic pathway have not been described yet. Our present results on Arabidopsis thaliana cell cultures suggest that acrolein, a lipid peroxide-derived reactive carbonyl species, is involved in plant ferroptosis-like cell death. The acrolein induced cell death could be mitigated by the known ferroptosis inhibitors such as Ferrostatin-1, Deferoxamine, α-Tocopherol, and glutathione. At the same time acrolein can be a mediator of ferroptosis-like cell death in plant cells since the known ferroptosis inducer RSL3 induced cell death could be mitigated by the acrolein scavenger carnosine. Finally, on the contrary to the caspase independent ferroptosis in human cells, we found that caspase-like activity can be involved in plant ferroptosis-like cell death.


Assuntos
Acroleína/metabolismo , Arabidopsis/fisiologia , Caspases/metabolismo , Ferroptose/fisiologia , Proteínas de Plantas/metabolismo , Acroleína/antagonistas & inibidores , Arabidopsis/citologia , Arabidopsis/efeitos dos fármacos , Carbolinas/farmacologia , Carnosina/farmacologia , Técnicas de Cultura de Células , Células Cultivadas , Cicloexilaminas/farmacologia , Desferroxamina/farmacologia , Ferroptose/efeitos dos fármacos , Glutationa/metabolismo , Ferro/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/fisiologia , Fenilenodiaminas/farmacologia
15.
Sci Rep ; 9(1): 19703, 2019 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-31873149

RESUMO

Benign prostatic hyperplasia (BPH) is one of the most common diseases in the urinary system of elderly men. Pao extract is an herbal preparation of the bark of the Amazon rainforest tree Pao Pereira (Geissospermum vellosii), which was reported to inhibit prostate cancer cell proliferation. Herein we investigated the therapeutic potential of Pao extract against BPH development in a testosterone-induced BPH rat model. The administration of testosterone induced the prostate enlargement, compared with the sham operated group with vehicle treatment. The BPH/Pao group showed reduced prostate weight comparable with BPH/finasteride group. Notably, Pao treatment did not significantly reduce body weights and sperm number of rats, compared with the control group. Furthermore, Pao extract treatment reduced the proliferative index in prostate glands and testosterone-induced expression levels of AR, as well as androgen-associated proteins such as SRD5A1 and PSA. Moreover, Pao extract and its active component, flavopereirine, induced cytotoxicity on human prostate epithelial RWPE-1 cells in a dose- and time- dependent manner with G2/M arrest. Consistently, Pao extract and flavopereirine suppressed the expression levels of SRD5A1, AR and PSA, respectively. Together, these data demonstrated that Pao extract suppresses testosterone-induced BPH development through inhibiting AR activity and expression, and suggested that Pao extract may be a promising and relative safe agent for BPH.


Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Apocynaceae/química , Colestenona 5 alfa-Redutase/metabolismo , Extratos Vegetais/farmacologia , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/tratamento farmacológico , Animais , Carbolinas/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Regulação para Baixo/genética , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Masculino , Extratos Vegetais/uso terapêutico , Próstata/efeitos dos fármacos , Próstata/metabolismo , Próstata/patologia , Antígeno Prostático Específico/metabolismo , Hiperplasia Prostática/genética , Hiperplasia Prostática/patologia , Ratos Sprague-Dawley , Receptores Androgênicos/metabolismo , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Testosterona
16.
Molecules ; 24(22)2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31703464

RESUMO

Portulaca oleracea is as a medicinal plant known for its neuroprotective, hepatoprotective, antidiabetic, antioxidant, anticancer, antimicrobial, antiulcerogenic, and anti-inflammatory activities. However, the specific active compounds responsible for the individual pharmacological effects of P. oleracea extract (95% EtOH) remain unknown. Here, we hypothesized that alkaloids, the most abundant constituents in P. oleracea extract, are responsible for its anti-inflammatory activity. We investigated the phytochemical substituents (compounds 1-22) using nuclear magnetic resonance (NMR) and electrospray ionization mass spectrometry (ESI-MS) and screened their effects on NO production in lipopolysaccharide (LPS)-induced macrophages. Compound 20, 1-carbomethoxy-ß-carboline, as an alkaloid structure, ameliorated nitric oxide (NO) production, inducible nitric oxide synthase (iNOS), and proinflammatory cytokines associated with the mitogen-activated protein kinase (MAPK) pathways, p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK). Subsequently, we observed that compound 20 suppressed nuclear translocation of nuclear factor κB (NF-κB) using immunocytochemistry. Moreover, we recently reported that compound 8, trans-N-feruloyl-3', 7'-dimethoxytyramine, was originally purified from P. oleracea extracts. Our results suggest that 1-carbomethoxy-ß-carboline, the most effective anti-inflammatory agent among alkaloids in the 95% EtOH extract of P. oleracea, was suppressing the MAPK pathway and nuclear translocation of NF-κB. Therefore, P. oleracea extracts and specifically 1-carbomethoxy-ß-carboline may be novel therapeutic candidates for the treatment of inflammatory diseases associated with the activation of MAPKs and NF-κB.


Assuntos
Anti-Inflamatórios , Carbolinas , Núcleo Celular/metabolismo , Lipopolissacarídeos/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/metabolismo , Portulaca/química , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Carbolinas/química , Carbolinas/isolamento & purificação , Carbolinas/farmacologia , Núcleo Celular/patologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , MAP Quinase Quinase 4/metabolismo , Camundongos , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
17.
J Agric Food Chem ; 67(46): 12844-12853, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31668063

RESUMO

Flazin is a ß-carboline-derived alkaloid found in Japanese fermented foods. Here, the potential of flazin as an antioxidant food was studied with particular reference to its effect on the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) system in human hepatocytes (C3A). Flazin and flazin analogues including the decarboxylated derivative perlolyrine were chemically synthesized and compared with each other and with chlorogenic acid and curcumin. Among these compounds, flazin showed the lowest cytotoxicity (IC50 < 500 µM) and the highest capacity to activate the Keap1-Nrf2 system. It provided the largest (>3-fold of the control) cytoprotection ability against a pro-oxidant, although its radical absorbance capacity was relatively low. Flazin increased the expressions of Nrf2-dependent phase II enzyme genes and their products (NQO1, GSTP, and GSH proteins). The strong cytoprotection ability of flazin associated with low log P (0-3) is shared by sulforaphane and 3,5-dihydroxy-4-methoxybenzyl alcohol, suggesting the potential value of flazin and flazin-rich foods for the prevention of oxidation-related health disorders.


Assuntos
Carbolinas/farmacologia , Furanos/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/genética , Transdução de Sinais/efeitos dos fármacos
18.
Fitoterapia ; 139: 104375, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31629050

RESUMO

Picrasamide A (1), a new cinnamamide derivative, together with two new ß-carboline alkaloids (2 and 3) and five known ß-carboline alkaloids (4-8) were isolated from the stems of Picrasma quassioides (D. Don) Benn. Their structures were elucidated by detailed analyses of UV, IR, HRESIMS, and NMR data. Compound 1 was the first case of cinnamamide derivative from genus Picrasma. The AChE inhibitory activity and the antimicrobial activity of 1-8 were assessed. In addition, preliminary structure-activity relationships of these ß-carboline alkaloids on the AChE inhibitory activity and antimicrobial activity were proposed.


Assuntos
Antibacterianos/farmacologia , Inibidores da Colinesterase/farmacologia , Cinamatos/farmacologia , Picrasma/química , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Antibacterianos/isolamento & purificação , Carbolinas/isolamento & purificação , Carbolinas/farmacologia , China , Inibidores da Colinesterase/isolamento & purificação , Cinamatos/isolamento & purificação , Testes de Sensibilidade Microbiana , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Caules de Planta/química , Relação Estrutura-Atividade
19.
Eur J Pharmacol ; 863: 172658, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31518562

RESUMO

Breast cancer, which is the most frequently diagnosed cancer, is quite heterogeneous. For breast cancer subtypes lacking targeted therapies, it is vitally essential to find novel agents that prevent chemoresistance and metastatic relapse. Flavopereirine is a ß-carboline alkaloid that has antiplasmodial activity, and its antiproliferative effect in different cancers remains unclear. The effect of flavopereirine on cell cycle arrest and apoptosis signaling in breast cancer cells was analyzed by flow cytometry. An inhibitor and siRNA were used to confirm the related signaling pathways by Western blot analysis. We found that flavopereirine caused G0/G1 phase arrest in MCF-7 cells and S phase arrest in MDA-MB-231 cells. MDA-MB-231 cells were more sensitive to flavopereirine-induced apoptosis. Furthermore, we found that flavopereirine-induced apoptosis was partially reduced in MDA-MB-231 cells treated with an extracellular regulated kinase (ERK) inhibitor and p38 mitogen-activated protein kinase (MAPK) siRNA. Moreover, p38 siRNA treatment simultaneously reduced phosphorylated ERK expression levels. Conversely, the recovered phosphorylation of AKT decreased the levels of p-ERK and p-p38 MAPK. Overall, flavopereirine induces cell cycle arrest and the AKT/p38 MAPK/ERK signaling pathway, which contribute to flavopereirine-induced apoptosis in MDA-MB-231 cells.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Carbolinas/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Células MCF-7 , Mitocôndrias/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
20.
Molecules ; 24(16)2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31416271

RESUMO

Utilizing a pharmacophore hybridization approach, we have designed and synthesized a novel series of 28 new heterobivalent ß-carbolines. The in vitro cytotoxic potential of each compound was evaluated against the five cancer cell lines (LLC, BGC-823, CT-26, Bel-7402, and MCF-7) of different origin-murine and human, with the aim of determining the potency and selectivity of the compounds. Compound 8z showed antitumor activities with half-maximal inhibitory concentration (IC50) values of 9.9 ± 0.9, 8.6 ± 1.4, 6.2 ± 2.5, 9.9 ± 0.5, and 5.7 ± 1.2 µM against the tested five cancer cell lines. Moreover, the effect of compound 8z on the angiogenesis process was investigated using a chicken chorioallantoic membrane (CAM) in vivo model. At a concentration of 5 µM, compound 8z showed a positive effect on angiogenesis. The results of this study contribute to the further elucidation of the biological regulatory role of heterobivalent ß-carbolines and provide helpful information on the development of vascular targeting antitumor drugs.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Carbolinas/síntese química , Carbolinas/farmacologia , Desenho de Fármacos , Hidrazonas/química , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/química , Carbolinas/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Química Sintética , Embrião de Galinha , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Neovascularização Patológica/tratamento farmacológico , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA