RESUMO
In our previous study, we designed a series of pyrazole derivatives as novel COX-2 inhibitors. In order to obtain novel dual inhibitors of COX-2 and 5-LOX, herein we designed and synthesized 20 compounds by hybridizing pyrazole with substituted coumarin who was reported to exhibit 5-LOX inhibition to select potent compounds using adequate biological trials sequentially including selective inhibition of COX-2 and 5-LOX, anti-proliferation in vitro, cells apoptosis and cell cycle. Among them, the most potent compound 11g (IC50=0.23±0.16µM for COX-2, IC50=0.87±0.07µM for 5-LOX, IC50=4.48±0.57µM against A549) showed preliminary superiority compared with the positive controls Celecoxib (IC50=0.41±0.28µM for COX-2, IC50=7.68±0.55µM against A549) and Zileuton (IC50=1.35±0.24µM for 5-LOX). Further investigation confirmed that 11g could induce human non-small cell lung cancer A549 cells apoptosis and arrest the cell cycle at G2 phase in a dose-dependent manner. Our study might contribute to COX-2, 5-LOX dual inhibitors thus exploit promising novel cancer prevention agents.
Assuntos
Cumarínicos/química , Cumarínicos/farmacologia , Ciclo-Oxigenase 2/metabolismo , Pirazóis/química , Pirazóis/farmacologia , Células A549 , Apoptose/efeitos dos fármacos , Araquidonato 5-Lipoxigenase/química , Araquidonato 5-Lipoxigenase/metabolismo , Sítios de Ligação , Domínio Catalítico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/farmacologia , Simulação de Acoplamento Molecular , Relação Estrutura-AtividadeRESUMO
Acute lung injury (ALI) is a serious pulmonary inflammatory disease resulting from excessive reactive oxygen species (ROS) which could cause the damage of the alveolar epithelial cells and capillary endothelial cells. Peroxynitrite, as one of short-lived reactive oxygen species, is closely related to the process of ALI. Thus, it is important to monitor the fluctuation of peroxynitrite in living system for understanding the process of ALI. Herein, the novel mitochondria-targeted fluorescent probe BHMT was designed to respond to peroxynitrite and pH with distinct fluorescence properties respectively. The absorption spectrum of the probe BHMT exhibited a notable red shift as the pH value declined from 8.8 to 2.6. Upon reaction with peroxynitrite, BHMT had a significant increase of fluorescence intensity (63-fold) with maintaining a detection limit of only 43.7 nM. Furthermore, BHMT could detect the levels of endogenous peroxynitrite and image the intracellular pH in ratiometric channels utilizing cell imaging. In addition, BHMT was successfully applied to revealing the relationship between the peroxynitrite and the extent of ALI. Thus, these results indicated the probe BHMT could be a potential tool for diagnosing the early stage of ALI and revealed the peroxynitrite was likely to be a crucial therapeutic target in ALI treatment.
RESUMO
Photodynamic therapy (PDT) under hypoxic conditions and drug resistance in chemotherapy are perplexing problems in anti-tumor treatment. In addition, central nervous system neoplasm-targeted nanoplatforms are urgently required. To address these issues, a new multi-functional protein hybrid nanoplatform is designed, consisting of transferrin (TFR) as the multicategory solid tumor recognizer and hemoglobin for oxygen supply (ODP-TH). This protein hybrid framework encapsulates the photosensitizer protoporphyrin IX (PpIX) and chemotherapeutic agent doxorubicin (Dox), which are attached by a glutathione-responsive disulfide bond. Mechanistically, ODP-TH crosses the blood-brain barrier (BBB) and specifically aggregated in hypoxic tumors via protein homology recognition. Oxygen and encapsulated drugs ultimately promote a therapeutic effect by down-regulating the abundance of multidrug resistance gene 1 (MDR1) and hypoxia-inducible factor-1-α (HIF-1α). The results reveal that ODP-TH achieves oxygen transport and protein homology recognition in the hypoxic tumor occupation. Indeed, compared with traditional photodynamic chemotherapy, ODP-TH achieves a more efficient tumor-inhibiting effect. This study not only overcomes the hypoxia-related inhibition in combination therapy by targeted oxygen transport but also achieves an effective treatment of multiple tumors, such as breast cancer and glioma, providing a new concept for the construction of a promising multi-functional targeted and intensive anti-tumor nanoplatform.
Assuntos
Carcinoma , Fotoquimioterapia , Feminino , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/terapia , Carcinoma/tratamento farmacológico , Carcinoma/terapia , Hipóxia , Oxigênio/farmacologia , Oxigênio/uso terapêutico , Fármacos Fotossensibilizantes/química , Fotoquimioterapia/instrumentação , Fotoquimioterapia/métodos , Nanotecnologia/instrumentação , Nanotecnologia/métodos , Nanomedicina/instrumentação , Nanomedicina/métodosRESUMO
Theranostic prodrug was highly desirable for precise diagnosis and anti-cancer therapy to decrease side effects. However, it is difficult to conjugate chemo-drug and molecular probe for combined therapy due to the complex pharmacokinetics of different molecules. Here, a novel anticancer theranostic prodrug (BTMP-SS-PTX) had been designed and synthesized by conjugating paclitaxel (PTX) with 2-(benzo[d]thiazol-2-yl)-4-methoxyphenol (BTMP) through a disulphide (-S-S-) linkage, which was redox-sensitive to the high concentration of glutathione in tumors. Upon activation with glutathione in weakly acid media, the BTMP-SS-PTX can be dissociated to release free PTX and visible BTMP, which realized the visual tracking of free drug. The cytotoxicity study demonstrated that soluble prodrug BTMP-SS-PTX displayed more outstanding anticancer activity in HepG2, MCF-7 and HeLa cells, lower toxicity to non-cancer cells (293 T) than free drugs. Furthermore, BTMP-SS-PTX was still able to induce apoptosis of HeLa cells and significantly inhibited tumor growth in HeLa-xenograft mouse model. On the basis of these findings, BTMP-SS-PTX could play a potential role in cancer diagnosis and therapy.
Assuntos
Antineoplásicos/farmacologia , Glutationa/farmacologia , Pró-Fármacos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Glutationa/química , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/tratamento farmacológico , Imagem Óptica , Pró-Fármacos/síntese química , Pró-Fármacos/química , Solubilidade , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
In this paper, 41 hybrid compounds containing diaryl-1,5-diazole and morpholine structures acting as dual COX-2/5-LOX inhibitors have been designed, synthesized and biologically evaluated. Most of them showed potent antiproliferative activities and COX-2/5-LOX inhibitory in vitro. Among them, compound A33 displayed the most potency against cancer cell lines (IC50â¯=â¯6.43-10.97⯵M for F10, HeLa, A549 and MCF-7â¯cells), lower toxicity to non-cancer cells than celecoxib (A33: IC50â¯=â¯194.01⯵M vs.celecoxib: IC50â¯=â¯97.87⯵M for 293T cells), and excellent inhibitory activities on COX-2 (IC50â¯=â¯0.17⯵M) and 5-LOX (IC50â¯=â¯0.68⯵M). Meanwhile, the molecular modeling study was performed to position compound A33 into COX-2 and 5-LOX active sites to determine the probable binding models. Mechanistic studies demonstrated that compound A33 could block cell cycle in G2 phase and subsequently induced apoptosis of F10â¯cells. Furthermore, compound A33 could significantly inhibit tumor growth in F10-xenograft mouse model, and pharmacokinetic study of compound A33 indicated that it showed better stability in vivo. In general, compound A33 could be a promising candidate for cancer therapy.
Assuntos
Antineoplásicos/farmacologia , Araquidonato 5-Lipoxigenase/metabolismo , Azóis/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Inibidores de Lipoxigenase/farmacologia , Morfolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Azóis/síntese química , Azóis/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Modelos Moleculares , Estrutura Molecular , Morfolinas/química , Relação Estrutura-AtividadeRESUMO
A series of novel ferrocene-pyrazole derivatives containing nitric oxide donors as COX-2 inhibitors for cancer therapy were designed, synthesized and biologically evaluated. Among them, compound 7l displayed the most potent inhibitory against COX-2 (IC50â¯=â¯0.82⯵M) and antiproliferative activities against Hela cells (IC50â¯=â¯0.34⯵M) compared with Celecoxib (IC50â¯=â¯0.38 and 7.91⯵M). The further mechanistic studies revealed that 7l could induce apoptosis of Hela cells by mitochondrial depolarization and the antiproliferative activities of 7l were positively correlated with the levels of intracellular NO release in Hela cells. Most notably, 7l could dramatically suppress tumor growth in Hela cells xenografted mouse model. In summary, compound 7l may be promising candidates for cancer therapy.
Assuntos
Antineoplásicos/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Desenho de Fármacos , Compostos Ferrosos/farmacologia , Metalocenos/farmacologia , Neoplasias Experimentais/tratamento farmacológico , Doadores de Óxido Nítrico/farmacologia , Pirazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Compostos Ferrosos/química , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Metalocenos/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/química , Pirazóis/química , Relação Estrutura-AtividadeRESUMO
Microtubules are essential for the mitotic division of cells and have become an attractive target for anti-tumour drugs due to the increased incidence of cancer and significant mitosis rate of tumour cells. In this study, a total of six indole 1-position modified 1-indolyl acetate-5-nitroimidazole derivatives were designed, synthesized, and evaluated for their ability to inhibit tubulin polymerization caused by binding to the colchicine-binding site of tubulin. Among them, compound 3 displayed the best ability to inhibit tubulin polymerization; it also exhibited better anti-proliferative activities than colchicine against a panel of human cancer cells (with IC50 values ranging from 15 to 40nM), especially HeLa cells (with IC50 values of 15nM), based on the cellular cytotoxicity assay results. Moreover, cellular mechanism studies indicated that compound 3 could induce G2/M phase arrest and apoptosis of HeLa and MCF-7 cells, which were associated with alterations in the expression of cell cycle-checkpoint related proteins (Cyclin B1, Cdc2, and P21) and a reduction in the mitochondrial membrane potential as well as alterations in the levels of apoptosis-related proteins (PARP, Caspase 9, Bcl-2, and Bax) of these cells, respectively. Importantly, in vivo studies further revealed that compound 3 could dramatically suppress HeLa cell xenograft tumour growth compared with vehicle and CA-4 phosphate (CA-4P), and no signs of toxicity were observed in these mice. Collectively, these in vitro and in vivo results indicated that compound 3 might be a promising lead compound for further development as a potential anti-cancer drug.