Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
Mais filtros










Intervalo de ano de publicação
1.
Biochim Biophys Acta Gen Subj ; 1863(9): 1332-1342, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31170497

RESUMO

In a previous study, we described a series of 28 aryl- and alkyl-substituted isothiouronium salts with antitumor activity and selectivity toward a leukemia cell line. Among the synthesized compounds, methyl (Z)-2-(isothioureidomethyl)-2-pentenoate hydrobromide (IS-MF08) showed conspicuous activity. In the present study, we investigated the mechanism of action of IS-MF08. Our results showed that its mechanism most likely is related with the membrane receptor Fas and subsequent activation of the extrinsic cell death pathway, triggered by a decrease in the levels of the anti-apoptotic protein Bcl-2 and caspase-8 and -3 cascade activation, causing DNA damage and mitotic arrest. IS-MF08 also caused an increase in intracellular ROS, endoplasmic reticulum (ER) stress, and mitochondrial membrane permeabilization, resulting in organelle degradation as an attempt to reestablish cell homeostasis. Furthermore, cells exposed to IS-MF08 combined to an autophagy inhibitor were less susceptible to compound's cytotoxicity, suggesting that autophagy makes part of its mechanism of action. These data support the hypothesis that IS-MF08 acts by the apoptosis extrinsic pathway and possibly by autophagy as mechanisms of cell death.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Isotiurônio/farmacologia , Leucemia/patologia , Mitose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos
2.
Eur J Med Chem ; 129: 151-158, 2017 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-28222315

RESUMO

A series of 28 aryl- and alkyl-substituted isothiouronium salts were readily synthesized in high yields through the reaction of allylic bromides with thiourea, N-monosubstituted thioureas or thiosemicarbazide. The S-allylic isothiouronium salts substituted with aliphatic groups were found to be the most effective against leukemia cells. These compounds combine high antitumor activity and low toxicity toward non-tumoral cells, with selectivity index higher than 20 in some cases. Furthermore, the selected isothiouronium salts induced G2/M cell cycle arrest and cell death, possibly by apoptosis. Therefore, these compounds can be considered as a promising class of antitumor agents due to the potent cytostatic activity associated with high selectivity.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Isotiurônio/síntese química , Isotiurônio/farmacologia , Tioureia/análogos & derivados , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Humanos , Relação Estrutura-Atividade
3.
Anticancer Agents Med Chem ; 15(3): 353-62, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25469513

RESUMO

Melanoma is a very aggressive type of skin cancer. Mutation in BRAF and NRAS are often found in patients with this disease. Therefore, in recent years the search for new molecules that inhibit these proteins has been intensified. After many years with no new treatments for melanoma, the U.S. Food and Drug Administration (FDA) recently approved vemurafenib. However, many patients have already acquired resistance and have experienced severe side effects. Therefore, this work aims to evaluate a new set of compounds including allylic isothiouronium salts (1, 2 and 3), N-phenyl-substituted analog (4) and isothiosemicarbazide salts (5 and 6) for their potential antimelanoma activity. To this end, viability assay, cell cycle analysis, expression of NRAS and BRAF, as well as migration and invasion assay were performed with different melanoma cell lines. Isothiouronium salts 1-3 presented CC50 (concentration required to reduce the cell number by 50%) in a range of 7-28 µM. Furthermore, salt 1 significantly decreased the expression of NRAS. However, cells incubated with these salts did not disturb the cell cycle phases; instead, an increase in the number of apoptotic cells was observed. Regarding potential antiinvasion effects, both 1 and 2 prevented cell migration as well as cell invasion. Finally, when salts 1 and 2 were associated with vemurafenib, a marked decrease in cell viability was observed when compared to the compounds incubated alone. Briefly, the salts exhibited interesting results, especially 1, which decreased the expression of NRAS, increased apoptotic cells and, when combined with vemurafenib, resulted in a synergistic effect. Therefore, we intend to test compound 1 in pre-clinical studies.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , GTP Fosfo-Hidrolases/antagonistas & inibidores , Isotiurônio/farmacologia , Melanoma/tratamento farmacológico , Proteínas de Membrana/antagonistas & inibidores , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Humanos , Isotiurônio/química , Melanoma/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Estrutura Molecular , Invasividade Neoplásica/patologia , Sais/química , Sais/farmacologia , Relação Estrutura-Atividade , Células Tumorais Cultivadas
4.
Braz J Microbiol ; 45(3): 807-12, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25477911

RESUMO

Bacterial resistance to commonly used antibiotics has been recognized as a significant global health issue. In this study, we carried out the screening of a family of allylic thiocyanates for their action against a diversity of bacteria and fungi with a view to developing new antimicrobial agents. Allylic thiocyanates bearing halogenated aryl groups, which were readily obtained in two steps from the Morita-Baylis-Hillman adducts, showed moderate-to-high activity against selective pathogens, including a methicillin-resistant S. aureus (MRSA) strain. In particular cases, methyl (Z)-3-(2,4-dichlorophenyl)-2-(thiocyanomethyl)-2-propenoate exhibited antimicrobial activity comparable to the reference antibiotic Imipenem.


Assuntos
Compostos Alílicos/farmacologia , Anti-Infecciosos/farmacologia , Bactérias/efeitos dos fármacos , Fungos/efeitos dos fármacos , Tiocianatos/farmacologia , Compostos Alílicos/síntese química , Testes de Sensibilidade Microbiana , Tiocianatos/síntese química
5.
Braz. j. microbiol ; 45(3): 807-812, July-Sept. 2014. ilus, tab
Artigo em Inglês | LILACS | ID: lil-727006

RESUMO

Bacterial resistance to commonly used antibiotics has been recognized as a significant global health issue. In this study, we carried out the screening of a family of allylic thiocyanates for their action against a diversity of bacteria and fungi with a view to developing new antimicrobial agents. Allylic thiocyanates bearing halogenated aryl groups, which were readily obtained in two steps from the Morita-Baylis-Hillman adducts, showed moderate-to-high activity against selective pathogens, including a methicillin-resistant S. aureus (MRSA) strain. In particular cases, methyl (Z)-3-(2,4-dichlorophenyl)-2-(thiocyanomethyl)-2-propenoate exhibited antimicrobial activity comparable to the reference antibiotic Imipenem.


Assuntos
Compostos Alílicos/farmacologia , Anti-Infecciosos/farmacologia , Bactérias/efeitos dos fármacos , Fungos/efeitos dos fármacos , Tiocianatos/farmacologia , Compostos Alílicos/síntese química , Testes de Sensibilidade Microbiana , Tiocianatos/síntese química
6.
Eur J Med Chem ; 70: 411-8, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24177368

RESUMO

2-Amino-1,3-thiazin-4-ones were subjected to acetylation followed by mild acid hydrolysis to give compounds containing the 1,3-thiazine-2,4-dione core. The potential of these S,N-containing heterocycles as antitumor agents against human cancer cell lines, among other types, was evaluated. The results show that phenyl- and naphthyl-substituted thiazinediones presented selective antitumoral activity against leukemia cells. These compounds caused cell death with DNA fragmentation and the mechanism of action seems to involve caspase cascade activation, imbalance in intracellular Ca(2+) and mitochondrial metabolism, and/or endoplasmic reticulum stress.


Assuntos
Antineoplásicos/farmacologia , Triazinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Fragmentação do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/química , Células Vero
7.
Bioorg Med Chem Lett ; 22(20): 6486-9, 2012 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-22967767

RESUMO

TB is a global public health emergency in which new drugs are desperately needed. Herein we report on the synthesis of a diverse panel of 41 aryl allylic azides, thiocyanates, isothiouronium salts, and N,N'-diacetylisothioureas that were evaluated for their in vitro activity against replicating and non-replicating Mycobacterium tuberculosis (Mtb) H(37)Rv and toxicity to VERO cells. We found a selective group of new and promising compounds having good (micromolar) to excellent (sub-micromolar) potency against replicating Mtb H(37)Rv. Allylic thiocyanates bearing halophenyl (halo=2-Br, 4-Br, 4-Cl, 4-F), 4-methylphenyl and 2-naphthyl moieties were the most active as antitubercular agents. In particular, the 2-bromophenyl-substituted thiocyanate showed MIC=0.25 µM against replicating Mtb, MIC=8.0 µM against non-replicating Mtb and IC(50)=32 µM in the VERO cellular toxicity assay.


Assuntos
Compostos Alílicos/química , Compostos Alílicos/farmacologia , Antituberculosos/química , Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tiocianatos/química , Tiocianatos/farmacologia , Tuberculose/tratamento farmacológico , Compostos Alílicos/toxicidade , Animais , Antituberculosos/toxicidade , Chlorocebus aethiops , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/crescimento & desenvolvimento , Tiocianatos/toxicidade , Tuberculose/microbiologia , Células Vero
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...