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1.
Crit Care Med ; 47(9): e735-e743, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31162191

RESUMO

OBJECTIVES: To investigate whether XueBiJing injection improves clinical outcomes in critically ill patients with severe community-acquired pneumonia. DESIGN: Prospective, randomized, controlled study. SETTING: Thirty-three hospitals in China. PATIENTS: A total of 710 adults 18-75 years old with severe community-acquired pneumonia. INTERVENTIONS: Participants in the XueBiJing group received XueBiJing, 100 mL, q12 hours, and the control group received a visually indistinguishable placebo. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 8-day improvement in the pneumonia severity index risk rating. Secondary outcomes were 28-day mortality rate, duration of mechanical ventilation and total duration of ICU stay. Improvement in the pneumonia severity index risk rating, from a previously defined endpoint, occurred in 203 (60.78%) participants receiving XueBiJing and in 158 (46.33%) participants receiving placebo (between-group difference [95% CI], 14.4% [6.9-21.8%]; p < 0.001). Fifty-three (15.87%) XueBiJing recipients and 84 (24.63%) placebo recipients (8.8% [2.4-15.2%]; p = 0.006) died within 28 days. XueBiJing administration also decreased the mechanical ventilation time and the total ICU stay duration. The median mechanical ventilation time was 11.0 versus 16.5 days for the XueBiJing and placebo groups, respectively (p = 0.012). The total duration of ICU stay was 12 days for XueBiJing recipients versus 16 days for placebo recipients (p = 0.004). A total of 256 patients experienced adverse events (119 [35.63%] vs 137 [40.18%] in the XueBiJing and placebo groups, respectively [p = 0.235]). CONCLUSIONS: In critically ill patients with severe community-acquired pneumonia, XueBiJing injection led to a statistically significant improvement in the primary endpoint of the pneumonia severity index as well a significant improvement in the secondary clinical outcomes of mortality, duration of mechanical ventilation and duration of ICU stay.

2.
Analyst ; 143(20): 4860-4869, 2018 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-30128454

RESUMO

Monitoring the fluctuations of endogenous selenocysteine (Sec) in vivo is of significant interest to understand the physiological roles of Sec and the mechanisms of Sec-relevant diseases. Herein, a new near-infrared fluorescent probe, Fsec-1, has been developed for the determination of endogenous Sec in living cells and in vivo. Fsec-1 exhibits large fluorescence enhancement (136-fold) and a remarkably large Stokes shift (195 nm) when reacted with Sec. With the advantages of high sensitivity (a detection limit of 10 nM), good selectivity and low cytotoxicity, Fsec-1 was able to recognize both exogenous and endogenous Sec in living cells. The probe was also successfully applied in visualizing both exogenous and endogenous Sec in living mice. Notably, endogenously generated Sec in living tumors xenografted in nude mice was selectively detected by our reaction-based NIR probe for the first time. These results indicated that our new probe could serve as an efficient tool in monitoring endogenous Sec in vivo and exploring the anticancer mechanism of selenium.


Assuntos
Corantes Fluorescentes/química , Neoplasias/química , Nitrilos/química , Selenocisteína/análise , Animais , Estabilidade de Medicamentos , Feminino , Fluorescência , Corantes Fluorescentes/síntese química , Xenoenxertos , Humanos , Limite de Detecção , Células MCF-7 , Masculino , Camundongos Nus , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Transplante de Neoplasias , Nitrilos/síntese química , Imagem Óptica/métodos , Selenocisteína/metabolismo , Raios Ultravioleta
3.
J Enzyme Inhib Med Chem ; 32(1): 954-959, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28718674

RESUMO

The epidermal growth factor receptor (EGFR) and HER2 are two important tyrosine kinases that play crucial roles in signal transduction pathways that regulate numerous cellular functions including proliferation, differentiation, migration, and angiogenesis. In the past 20 years, many proteomic methods have emerged as powerful methods to evaluate proteins in biological processes and human disease states. Among them, activity-based protein profiling (ABPP) is one useful approach for the functional analysis of proteins. In this study, a novel photoaffinity probe 11 was designed and synthesised to assess the target profiling of the reactive group in the photoaffinity probe 11. Biological evaluation was performed, and the results showed that the novel photoaffinity probe binds to EGFR and HER2 proteins and it hits targets by the reactive group.


Assuntos
Desenho de Drogas , Receptores ErbB/química , Marcadores de Fotoafinidade/química , Quinazolinas/química , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Marcadores de Fotoafinidade/síntese química , Quinazolinas/síntese química , Relação Estrutura-Atividade
4.
Eur J Med Chem ; 130: 393-405, 2017 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-28279846

RESUMO

In this study, a series of 4-anilinoquinazoline derivatives bearing amino acid moiety were designed, synthesized and evaluated for biological activities. The synthesized compounds were screened for anticancer activity against human hepatocellular carcinoma cell HepG2 using SRB assay. In vitro cell growth inhibition assays indicated that compound 6m exhibited moderate inhibitory activities only against human hepatocellular carcinoma cells HepG2 with IC50 of 8.3 µM. Synthetic derivatives showed excellent selectivity, such as compound 6m demonstrated a strong inhibition of EGFR (IC50 = 0.0032 µM), with selectivity of over 2000-fold over other kinases. Apoptosis analysis revealed that compound 6m caused obvious induction of cell apoptosis. 6m significantly down-regulated the expression of Bcl-2 and up-regulated the expression of Bax, decreased mitochondrial membrane potential (ΔΨm), promoted the mitochondrial cytochrome c release into the cytoplasm, activated caspase-3, and finally induced apoptosis of HepG2 cells. Molecular docking indicated that compound 6m could bind well with EGFR. Therefore, compound 6m may be a potential agent for cancer therapy deserving further research.


Assuntos
Aminoácidos/química , Antineoplásicos/química , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Quinazolinas/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Células Hep G2 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/química
5.
Eur J Med Chem ; 123: 21-30, 2016 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-27474920

RESUMO

Calixarene-based compounds are highly effective therapeutic agents against cancer. This study aims to prepare a series of calix [n]arene (n = 4, 6, 8) polyhydroxyamine derivatives (3a-3m) and to study their potential antitumor activities. The single crystal structure of calixs[4]arene derivative 3a was determined through X-ray diffraction. We assessed the ability of the prepared calix [n]arene polyhydroxyamine derivatives to induce cytotoxicity in six cancer cell lines by performing cancer cell growth inhibition assays. Results demonstrated that compounds 3a-3d achieved IC50 values ranging from 1.6 µM to 11.3 µM. Among the different compounds, 3a and 3b exerted the strongest cytotoxic effect in inhibiting the growth of SKOV3 cells. In relation to the underlying mechanisms of cytotoxic effects, cell cycle analysis revealed that the exposure of SKOV3 cells to 3a induced cell cycle arrest in the G0/G1 phase, suggesting a reduction in DNA synthesis. Immunofluorescent staining indicated that the protein expression levels of caspase-3 and p53 in cells significantly increased, whereas that of Bcl-2 was effectively suppressed. Meanwhile, no significant changes in Bax were observed in SKOV3 cells. These results highlight that calixarene 3a can be further studied as a potential anticancer agent.


Assuntos
Antineoplásicos/química , Calixarenos/química , Animais , Antineoplásicos/farmacologia , Calixarenos/síntese química , Calixarenos/farmacologia , Caspase 3/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cristalografia por Raios X , Citostáticos/síntese química , Citostáticos/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/efeitos dos fármacos
6.
Molecules ; 21(4): 396, 2016 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-27023495

RESUMO

Human peptide deformylase (HsPDF) is an important target for anticancer drug discovery. In view of the limited HsPDF, inhibitors were reported, and high-throughput virtual screening (HTVS) studies based on HsPDF for developing new PDF inhibitors remain to be reported. We reported here on diverse small molecule inhibitors with excellent anticancer activities designed based on HTVS and molecular docking studies using the crystal structure of HsPDF. The compound M7594_0037 exhibited potent anticancer activities against HeLa, A549 and MCF-7 cell lines with IC50s of 35.26, 29.63 and 24.63 µM, respectively. Molecular docking studies suggested that M7594_0037 and its three derivatives could interact with HsPDF by several conserved hydrogen bonds. Moreover, the pharmacokinetic and toxicity properties of M7594_0037 and its derivatives were predicted using the OSIRIS property explorer. Thus, M7594_0037 and its derivatives might represent a promising scaffold for the further development of novel anticancer drugs.


Assuntos
Amidoidrolases/química , Antineoplásicos/química , Neoplasias/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/química , Amidoidrolases/antagonistas & inibidores , Antineoplásicos/administração & dosagem , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Células HeLa , Humanos , Ligações de Hidrogênio/efeitos dos fármacos , Células MCF-7 , Simulação de Acoplamento Molecular , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/administração & dosagem
7.
Biomed Pharmacother ; 75: 185-90, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26337230

RESUMO

BACKGROUND: MicroRNA (miR)-365 functions as a tumor suppressor in non-small cell lung cancer (NSCLC) cells by targeting thyroid transcription factor 1 (TTF-1). AIM: To investigate miR-365 and TTF-1 mRNA expression in serum of NSCLC and their associations with patients' prognosis. METHODS: MiR-365 and TTF-1 mRNA expression in 100 NSCLCs and 100 healthy control sera were detected by quantitative real-time PCR (qRT-PCR). RESULTS: MiR-365 expression level was significantly lower in NSCLC serum samples than in healthy control serum samples (P<0.001), while TTF-1 mRNA expression level was significantly increased in NSCLC serum samples compared to healthy control serum samples (P<0.001). In addition, low miR-365 expression and high TTF-1 expression, alone or in combination, were all significantly associated with poor differentiation (P=0.008, 0.008 and 0.001, respectively), advanced TNM stage (P=0.001, 0.005 and <0.001 respectively) and positive lymph node metastasis (P=0.02, 0.02 and 0.01, respectively) of NSCLC patients. Notably, NSCLC patients with combined low miR-365 expression and high TTF-1 expression (miR-365-low/TTF-1-high) had shortest overall survival (P<0.001). Furthermore, multivariate analysis showed that miR-365 expression (P=0.01), TTF-1 expression (P=0.01), and combined expression of miR-365 and TTF-1 (miR-365/TTF-1, P=0.001) were all independent prognostic factors for overall survival in NSCLC patients. CONCLUSIONS: Our data reveal that preoperative serum miR-365 and TTF-1 mRNA levels may be both effective indicators of tumor aggressiveness in human NSCLC. More interestingly, miR-365 and its target gene TTF-1 appear to be synergistic risk factors for the reduction in overall survival of patients with NSCLC.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Neoplasias Pulmonares/sangue , MicroRNAs/sangue , Proteínas Nucleares/sangue , RNA Mensageiro/sangue , Fatores de Transcrição/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/secundário , Estudos de Casos e Controles , Diferenciação Celular , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Metástase Linfática , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Proteínas Nucleares/genética , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Risco , Fator Nuclear 1 de Tireoide , Fatores de Tempo , Fatores de Transcrição/genética
8.
Food Chem ; 171: 89-97, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25308647

RESUMO

The free radical scavenging activity of a series of 2,4,5-trimethoxy chalcones has been computationally explored using the density functional theory (DFT) method. Three potential working mechanisms, hydrogen atom transfer (HAT), stepwise electron transfer proton transfer (SET-PT) and sequential proton loss electron transfer (SPLET) have been investigated. The physiochemical parameters including O-H bond dissociation enthalpy (BDE), ionisation potential (IP), proton dissociation enthalpy (PDE), proton affinity (PA) and electron transfer enthalpy (ETE) have been calculated in gas phase and solvents. The order of antioxidant efficiencies predicted theoretically in this work is in good agreement with that reported by experimental results. The results obtained demonstrate that HAT would be the most favourable mechanism in the gas and benzene phases, whereas the SPLET mechanism is the thermodynamically preferred pathway in polar media. In addition, the importance of the A-ring on the radical scavenging capabilities of chalcones was also confirmed.


Assuntos
Antioxidantes/química , Chalconas/química , Transporte de Elétrons , Depuradores de Radicais Livres/química , Oxirredução , Polifenóis/química , Solventes/química , Termodinâmica
9.
Int J Clin Exp Pathol ; 8(11): 14983-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26823832

RESUMO

OBJECTIVE: MiRNAs play crucial roles in progression of cancer. However, the underlying mechanisms of miRNAs in non small cell lung cancer are still poorly understood. The aim of this study was to investigate the expression level of microRNA-126 (miR-126) and microRNA-133b (miR-133b) and also their association with clinicopathological features in patients with non small cell lung cancer (NSCLC). METHODS: Total RNA was purified from NSCLC tissues and adjacent non-tumor tissues and then quantitative real-time PCR (qRT-PCR) was used to evaluate the expression rate of microRNAs. Furthermore, the association of miR-126 and miR-133b level with clinicopathological features and prognosis were evaluated. RESULTS: Our findings showed that expression of miR-126 was decreased in NSCLC tissues compared with adjacent non-tumor tissues. On the other hand, a lower expression of miR-133b was seen in NSCLC tissues when compared with adjacent non-tumor tissues. In term of miR-126, our results showed that miR-126 was associated with tumor stage and lymph nodes metastasis (P<0.05). In term of miR-133b, our finding indicated that decreased expression of miR-133b was correlated with advanced tumor stage and lymph nodes metastasis (P<0.05). Kaplan-Meier analysis and log-rank test indicated that patients with low expression of miR-126 and miR-133b had a shorter overall survival (log-rank test; P<0.05). Multivariate Cox proportional hazards model revealed that low expression of miR-126 and miR-133b, advanced tumor stage and lymph nodes metastasis were independent prognostic factors for overall survival of NSCLC patients. CONCLUSIONS: These findings suggested that miR-126 and miR-133b might play a key role in the progression and metastasis of NSCLC and would be applied as a novel therapeutic agent.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Progressão da Doença , Intervalo Livre de Doença , Regulação para Baixo , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Metástase Linfática/genética , Metástase Linfática/patologia , Masculino , MicroRNAs , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Reação em Cadeia da Polimerase em Tempo Real
10.
Exp Ther Med ; 8(6): 1723-1726, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25371722

RESUMO

The aim of the present study was to investigate the effect of Avastin on the number and structure of tumor blood vessels of nude mice with A549 lung adenocarcinoma. A total of 30 nude mice were randomly divided into three groups, namely the control, the Avastin I (Avastin 3 mg/kg) and the Avastin II (Avastin 6 mg/kg) groups. Following treatment, ELISA was used to detect the expression level of vascular endothelial growth factor (VEGF) in tumor tissues. The microvascular density in tumor tissues and tumor vascular pericyte coverage was detected by immunofluorescence. The tumor growth and survival rate of mice in the three groups were also analyzed. Compared with the control group, the Avastin I and II groups exhibited significantly decreased VEGF levels and microvascular density in the tumor tissues, with the decrease in the Avastin II group being more prominent (P<0.05). After 7 days of treatment, the vascular pericyte coverage in the tumor tissues of mice in the Avastin I and II groups was significantly increased compared with that in the control group mice (P<0.05). Compared with the control group, the mice in the Avastin I and II groups exhibited a significantly decreased tumor growth rate and this effect was dose-dependent. The survival rate of mice in the Avastin I and II groups was significantly increased compared with that of the mice in the control group (P<0.05). In conclusion, Avastin significantly decreased the microvascular density of the tumor in nude mice with A549 lung adenocarcinoma and also significantly increased tumor vascular pericyte coverage, inhibited tumor growth and increased the survival rate of the mice, through its potent antiangiogenic activity.

11.
Med Oncol ; 31(9): 129, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25064732

RESUMO

microRNA (miR)-138 has been recognized as a potential tumor suppressor via regulating 3-phosphoinositide-dependent protein kinase-1 (PDK1) expression in non-small cell lung cancer (NSCLC) cells. The aim of this study was to investigate miR-138 and PDK1 mRNA expression in serum of NSCLC and their associations with patients' prognosis. miR-138 and PDK1 mRNA expressions in 100 NSCLCs and 100 healthy control sera were detected by quantitative real-time PCR. miR-138 expression level was significantly lower in NSCLC serum samples than in healthy control serum samples (P < 0.001), while PDK1 mRNA expression level was significantly increased in NSCLC serum samples compared to healthy control serum samples (P < 0.001). In addition, miR-138 downregulation and PDK1 upregulation were both significantly associated with advanced tumor-node-metastasis (TNM) stage (both P = 0.002) and positive lymph node metastasis (both P = 0.01) of NSCLC patients. Moreover, the overall survival of NSCLC patients with low miR-138 expression or high PDK1 mRNA expression was obviously shorter than those with high miR-138 expression or low PDK1 mRNA expression (both P < 0.001). Notably, NSCLC patients with combined miR-138 downregulation and PDK1 upregulation (miR-138-low/PDK1-high) had shortest overall survival (P < 0.001). Furthermore, multivariate analysis showed that miR-138 expression (P = 0.01), PDK1 expression (P = 0.01), and combined expression of miR-138 and PDK1 (miR-138/PDK1, P = 0.001) were all independent prognostic factors for overall survival in NSCLC patients. Deregulation of miR-138/PDK1 cascade may be implicated in carcinogenesis and cancer progression of human NSCLC. More importantly, miR-138 and PDK1 may synergistically predict patients' prognosis and their combination may represent a promising prognostic biomarker of human NSCLC.


Assuntos
Proteínas Quinases Dependentes de 3-Fosfoinositídeo/sangue , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Neoplasias Pulmonares/sangue , MicroRNAs/sangue , RNA Mensageiro/sangue , Proteínas Quinases Dependentes de 3-Fosfoinositídeo/genética , Proteínas Quinases Dependentes de 3-Fosfoinositídeo/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real
12.
Food Chem ; 151: 198-206, 2014 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-24423521

RESUMO

Quantum chemical calculations based on the density functional theory (DFT) have been employed to study the relationship between the structure and the antioxidant activity of four polyphenolic deoxybenzoins (DOBs) in solvents and the gas phase. The three main working mechanisms, H-atom transfer (HAT), single electron transfer-proton transfer (SET-PT) and sequential proton loss electron transfer (SPLET) have been investigated. The calculated results closely matched experimental values. The results obtained prove that for the HAT mechanism, the most efficient system possessed ortho-dihydroxy functionality. The results suggested that HAT would be the most favourable mechanism for explaining the radical-scavenging activity of polyphenolic DOBs in the gas phase, whereas the SPLET mechanism is the thermodynamically favourable pathway in polar solvents.


Assuntos
Benzoína/análogos & derivados , Antioxidantes , Benzoína/química , Oxirredução , Polifenóis , Prótons , Solventes/química
13.
J Mol Model ; 19(9): 3851-62, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23801254

RESUMO

The free radical scavenging activity of six 2'-hydroxychalcones has been studied in gas phase and solvents using the density functional theory (DFT) method. The three main working mechanisms, hydrogen atom transfer (HAT), stepwise electron-transfer-proton-transfer (ET-PT) and sequential-proton-loss-electron-transfer (SPLET) have been considered. The O-H bond dissociation enthalpy (BDE), ionization potential (IP), proton affinity (PA) and electron transfer energy (ETE) parameters have been computed in gas phase and solvents. The theoretical results confirmed the important role of the B ring in the antioxidant properties of hydroxychalcones. In addition, the calculated results matched well with experimental values. The results suggested that HAT would be the most favorable mechanism for explaining the radical-scavenging activity of hydroxychalcone in gas phase, whereas SPLET mechanism is thermodynamically preferred pathway in aqueous solution.


Assuntos
Antioxidantes/química , Chalconas/química , Modelos Teóricos , Elétrons , Hidrogênio/química , Conformação Molecular , Prótons , Solventes/química , Termodinâmica
14.
Bioorg Med Chem Lett ; 23(12): 3523-30, 2013 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-23664099

RESUMO

Novel pyrazole-benzimidazole derivatives have been designed and synthesized. The entire target compounds were determined against cancer cell lines U937, K562, A549, LoVo and HT29 and were screened for Aurora A/B kinase inhibitory activity in vitro. The compounds 7a, 7b, 7i, 7k and 7l demonstrated significant cancer cell lines and Aurora A/B kinase inhibitory activities. Molecular modeling studies suggested the derivatives have bound in the active site of Aurora A kinase through the formation of four hydrogen bonds. Quantum chemical studies were carried out on these compounds to understand the structural features essential for activity. The cellular activity of 7k was also tested by immunofluorescence.


Assuntos
Aurora Quinase A/antagonistas & inibidores , Aurora Quinase B/antagonistas & inibidores , Benzimidazóis/química , Benzimidazóis/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Aurora Quinase A/química , Aurora Quinase B/química , Benzimidazóis/síntese química , Linhagem Celular Tumoral , Desenho de Drogas , Humanos , Modelos Moleculares , Pirazóis/síntese química , Teoria Quântica , Relação Estrutura-Atividade
15.
Ren Fail ; 35(3): 367-73, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23362955

RESUMO

There is an increasing evidence that oxidative stress plays an important role in the pathogenesis of rhabdomyolysis-induced acute renal failure (ARF). In this study, protective effects of L-citrulline on glycerol-induced ARF in rats were investigated. Six groups of rats were employed in this study: group 1 served as a control; group 2 was only given glycerol (50%, 10 mL/kg, i.m.); group 3 was given glycerol plus dexamethasone (0.1 mg/kg, i.g.) as positive reference drug, starting at the same time as the glycerol injections; the last three groups were given glycerol plus L-citrulline (300, 600, and 900 mg/kg, i.g.) respectively, starting at the same time as the glycerol injections. The injections of glycerol were only once, and after glycerol injections the i.g. administrations of dexamethasone and L-citrulline were repeated every 24 h for 7 days. After 7 days of glycerol injections, the blood samples and kidney tissues were harvested for future biochemical and pathology analyses. The levels of creatinine (Cr) and urea nitrogen (BUN) in plasma, the content of malondialdehyde (MDA), glutathione (GSH), nitric oxide (NO), the activity of total nitric oxide synthase (TNOS), inducible nitric oxide synthase (iNOS), endothelial NO synthase (eNOS), and superoxide dismutase (SOD) were evaluated in kidney tissues. Consequently, administrations of L-citrulline improved an impaired intrarenal oxygenation and kidney function compared with the glycerol group, and prevented the renal oxidative stress damage as well as severe functional and morphological renal deterioration. Therefore, L-citrulline might have potential application in the amelioration of glycerol-induced ARF.


Assuntos
Lesão Renal Aguda/prevenção & controle , Citrulina/uso terapêutico , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/patologia , Animais , Dexametasona , Avaliação Pré-Clínica de Medicamentos , Glicerol , Rim/patologia , Masculino , Ratos , Ratos Sprague-Dawley
16.
Chem Biol Drug Des ; 81(3): 399-407, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23279802

RESUMO

Nine novel 4-aminoquinazoline derivatives were designed and synthesized. Biochemical and cellular analyses demonstrated that most of the derivatives exhibited a strong activity to inhibit Aurora A and B kinases and to suppress the proliferation of a panel of human tumor cell lines (U937, K562, A549, LoVo, and HT29). Quantum chemical studies were also carried out to determine the structural features of these compounds engaged in the inhibition of Aurora kinases.


Assuntos
Antineoplásicos/síntese química , Inibidores de Proteínas Quinases/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Teoria Quântica , Quinazolinas/química , Antineoplásicos/química , Antineoplásicos/toxicidade , Aurora Quinases , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células HT29 , Humanos , Células K562 , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/toxicidade , Estrutura Terciária de Proteína , Proteínas Serina-Treonina Quinases/metabolismo , Quinazolinas/síntese química , Quinazolinas/toxicidade , Relação Estrutura-Atividade
17.
Pharmacol Biochem Behav ; 103(3): 474-80, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23026061

RESUMO

The present study was aimed to investigate the effects of nizofenone administration on the chronic restraint stress-induced cognitive impairments in mice. Adult male mice were randomized into five groups: control group, nizofenone control group, chronic restraint stress group, and nizofenone treatment groups (3.0mg/kg and 9.0mg/kg). The changes of cognitive performances were examined by Morris water maze (MWM), open field and step-through tests. Our results showed that the cognitive performances in CRS group were markedly deteriorated, accompanied by noticeable alterations in oxidative parameters, acetylcholinesterase activity and catecholamines levels in the hippocampus and the prefrontal cortex. These changes could be reversed by nizofenone treatment. Moreover, CRS group showed higher corticosterone levels and lower catecholamines levels in the serum, which were reversed in the nizofenone treatment groups. Collectively, the present results suggested the potential of nizofenone in attenuating the CRS-induced cognitive impairments.


Assuntos
Transtornos Cognitivos/tratamento farmacológico , Imidazóis/farmacologia , Fármacos Neuroprotetores/farmacologia , Estresse Psicológico/tratamento farmacológico , Acetilcolinesterase/metabolismo , Animais , Antioxidantes/metabolismo , Aprendizagem da Esquiva/efeitos dos fármacos , Catecolaminas/metabolismo , Transtornos Cognitivos/complicações , Corticosterona/metabolismo , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Imidazóis/uso terapêutico , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Restrição Física/métodos , Estresse Psicológico/sangue , Estresse Psicológico/complicações , Estresse Psicológico/psicologia
18.
Med Chem ; 9(3): 340-50, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-22920155

RESUMO

Two series of novel phenylaminopyrimidine derivatives were designed and synthesized. All target compounds were determined against the human acute monocytic leukemia cell line U937 and the human chronic myeloid leukemia cell line K562 in vitro. Some of the target compounds demonstrated significant inhibitory activity against both cell lines. Compared with the control drug VX-680, 8a, 8e, 8g, 8h, 8j, and 8k demonstrated more potent antitumor activity. The structures of all target compounds were identified by 1H-NMR, 13C-NMR, IR, MS, and EA.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Desenho de Drogas , Pirimidinas/síntese química , Pirimidinas/farmacologia , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Células K562 , Piperazinas/química , Piperazinas/farmacologia , Pirimidinas/química , Células U937
19.
Chem Biol Drug Des ; 78(6): 932-40, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21895983

RESUMO

Here, we describe the design and synthesis of two series of 4-pyrrylamino quinazolines as new analogs of the epidermal growth factor receptor inhibitor gefitinib. In vitro antitumor activity of these novel compounds against pancreatic (Miapaca2) and prostate (DU145) cancer cell lines was evaluated. Compared with the parental gefitinib, all 18 derivatives show a greatly increased cytotoxicity to cancer cells. In vitro kinase inhibitory activity on epidermal growth factor receptor was also investigated. Among them, compounds GI-6, GII-4, GII-6, GII-8, and GII-9 are more potential receptor tyrosine kinase (RTK) inhibitors. Based on these results, we propose simple structure-activity relationship to provide information for designing and developing more potent antitumor agents.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Quinazolinas/síntese química , Quinazolinas/toxicidade , Antineoplásicos/química , Linhagem Celular Tumoral , Desenho de Drogas , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Gefitinibe , Humanos , Quinazolinas/química , Relação Estrutura-Atividade
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