RESUMO
OBJECTIVE: The objective of this study was to analyze the relationship between quantitative parameters of spectral CT and the Ki67 expression index of tumor cells in hepatocellular carcinoma (HCC). METHODS: A total of 19 patients who underwent preoperative spectral CT dual-phase enhancement and who were diagnosed with HCC by postoperative pathology were prospectively selected. Patients with ≥10% Ki67-positive tumor cells formed a high-Ki67 group, and those with <10% Ki67- positive cells formed a low-Ki67 group. The iodine concentrations (ICs) of the lesion and the descending aorta were measured during the arterial and venous phases. Relative iodine concentration (RIC) was calculated thus: RIC=IClesion/ICdescending aorta. CT values of the lesions at 40 and 70 keV were measured during the enhanced arterial and venous phases. The slope of the spectral curve (λ) was calculated thus: λ = (40 keV-70 keV) /(70-30). To compare the differences in quantitative parameters between the high- and low-Ki67 groups, either an independent samples t-test (normal distribution) or a Mann-Whitney U test (non-normal distribution) was used. Receiver operating characteristic curves were used to evaluate the effectiveness of spectral CT parameters in distinguishing between high-Ki67 and low-Ki67 groups. Pearson correlation analysis was used to evaluate the correlation between spectral CT quantitative parameters and Ki67 expression. RESULTS: IC, RIC and λ values for the high-Ki67 group in arterial and venous phases were higher than those for the low-Ki67 group, P < 0.05. IC, RIC, and λ values in the arterial phase were 0.83, 0.89, and 0.75, respectively; in the venous phase, the values of these three parameters were 0.76, 0.77, and 0.69, respectively. IC, RIC, and λ were positively correlated with Ki67 expression in both arterial and venous phases, with a highest correlation of 0.82 for arterial-phase RIC. CONCLUSION: The quantitative parameters of spectral CT in HCC were correlated with Ki67 expression. This finding may make it easier for clinicians to determine whether a tumor is high or low in Ki67 before surgery.
RESUMO
Pancreatic cancer is one of the human gastrointestinal malignancies with a high mortality and poor prognosis. Approximately eighty percent of patients are diagnosed with unresectable or metastatic disease. Thus, development of novel chemicals in the treatment of pancreatic cancer is imperative. This study aimed to investigate the anticancer effects of N,N'-di-(m-methylphenyi)-3,6-dimethyl-1,4-dihydro-1,2,4,5-tetrazine-1,4-dicarboamide (ZGDHu-1), a new tetrazine derivative, on the PANC-1 pancreatic cancer cell line and clarify the underlying molecular mechanism. Using an MTT assay, we found that ZGDHu-1 significantly suppressed the proliferation of PANC-1 cells in a time- and dose-dependent manner. Moreover, according to the morphological and flow cytometric analysis, the results indicated that ZGDHu-1 induced PANC-1 cell apoptosis and G2/M cell cycle arrest in a dose-dependent manner. In the western blot analysis, expression of the pro-apoptotic Bax gene was upregulated while the anti-apoptotic Bcl-2 gene was downregulated following treatment with ZGDHu-1. ZGDHu-1 also activated pro-caspase-3 and PARP and increased the expression of NF-κB inhibitor IκB. Furthermore, the expression levels of G2/M regulatory molecules such as cyclin B1 and cdc2 were decreased while that of Chk1 was increased. These results suggested that ZGDHu-1 suppressed the proliferation of pancreatic cancer cells, rendering it a potential therapeutic drug for the treatment of pancreatic cancer.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma/patologia , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Compostos Heterocíclicos com 1 Anel/farmacologia , Neoplasias Pancreáticas/patologia , Antineoplásicos/administração & dosagem , Proteínas Reguladoras de Apoptose/biossíntese , Proteínas Reguladoras de Apoptose/genética , Caspase 3/efeitos dos fármacos , Proteínas de Ciclo Celular/biossíntese , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ativação Enzimática/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Compostos Heterocíclicos com 1 Anel/administração & dosagem , Humanos , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genéticaRESUMO
The present study examined the effects of N,N'di(mmethylphenyi)3, 6dimethyl1, 4dihydro1,2,4,5tetrazine1,4dicarboamide (ZGDHu1), a novel oxazine derivative, in Kasumi1 cells. Following incubation with various concentrations of ZGDHu1, fluorescenceactivated cell sorting (FACS) was used in order to detect changes in mitochondrial membrane permeability in Kasumi1 cells. Western blot analysis was performed in order to analyze the expression of nuclear factorκB, inhibitor of κB and AML1/ETO. In addition FACS was used to analyze leukemia cell cycles and the expression levels of cyclin, cyclindependent kinases and cyclindependent kinase inhibitors in G2/M phase were determined using FACS and western blot analysis. The upregulation of reactive oxygen species production and mitochondrial membrane permeability was ascribed to apoptosis. The growth of Kasumi1 cells was inhibited through the downregulation of nuclear factorκB, degradation of AML1/ETO fusion protein and cell cycle arrest at the G2/M phase. This study documented that G2/M regulatory molecules, including cyclin B1, cell division control (cdc)2 and cdc25c were downregulated and checkpoint kinase 1 (CHK1), p53, p27, phosphocdc25c, phosphoCHK1 and phosphop53 were upregulated following treatment with ZGDHu1. In the present study, pretreatment with CHIR124, a selective CHK1 inhibitor, abrogated G2/M arrest via ZGDHu1. These results demonstrated the antitumor activity of ZGDHu1, which may therefore a potential target for further investigation and may be useful for the treatment of patients with t(8;21) acute myeloid leukemia.
Assuntos
Apoptose/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Compostos Heterocíclicos com 1 Anel/farmacologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem , Criança , Quinases Ciclina-Dependentes/metabolismo , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/metabolismo , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Proteínas Quinases/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismoRESUMO
3,6-Diaryl-dihydro-1,2,4,5-tetrazine derivatives were synthesized and their structures were confirmed by single-crystal X-ray diffraction. Monosubstituted dihydrotetrazines are the 1,4-dihydro structure, but disubstituted dihydrotetrazines are the 1,2-dihydro structure. The results of further research indicated there may be a rearrangement during the synthesis process of disubstituted dihydrotetrazines. Their antitumor activities were evaluated against A-549 and P388 cells in vitro. The results showed several compounds to be endowed with cytotoxicity in the low micromolar range. Two compounds were highly effective against A-549 cell and IC50 values were 0.575 and 2.08 µM, respectively. Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were carried out on 37 1,2,4,5-tetrazine derivatives with antitumor activity against A-549 cell. Models with good predictive abilities were generated with the cross validated q(2) values for CoMFA and CoMSIA being 0.744 and 0.757, respectively. Conventional r(2) values were 0.978 and 0.988, respectively, the predicted R(2) values were 0.916 and 0.898, respectively. The results provide the tool for guiding the design and synthesis of novel and more potent tetrazine derivatives.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Tetrazóis/química , Tetrazóis/farmacologia , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Humanos , Modelos Moleculares , Relação Quantitativa Estrutura-Atividade , Tetrazóis/síntese química , Células Tumorais Cultivadas , Difração de Raios XRESUMO
Chronic lymphocytic leukemia (CLL) is a low-grade lymphoid malignancy incurable with conventional modalities of chemotherapy. We aimed to examine the proapoptotic effects of a novel proteasome inhibitor, N,N'-di-(m-methylphenyi)-3,6- dimethyl-1,4-dihydro-1,2,4,5-tetrazine-1,4-dicarboamide (ZGDHu-1), on CLL cells. B lymphocytes were isolated from CLL patients and normal healthy controls, and treated with various concentrations of ZGDHu-1 for different days. CLL cell viability was detected by MTT assay. The apoptosis, mitochondrial membrane potential (∆ψm) and reactive oxidative species (ROS) were examined by flow cytometry. The expression of caspase-3 and Bcl-2/Bax ratio was detected by western blotting. ZGDHu-1 significantly reduced the viability of CLL cells and induced apoptosis in comparison to the control cells (both P<0.05). Normal peripheral B cells were resistant to the apoptosis-inducing effects of ZGDHu-1. Apoptosis induced by ZGDHu-1 was accompanied with generation of ROS, loss of ∆ψm, downregulation of Bcl-2 and increase of caspase-3 cleavage. Results of this study indicate that ZGDHu-1 is a promising specific treatment for CLL in the clinic.
Assuntos
Antineoplásicos/farmacologia , Compostos Heterocíclicos com 1 Anel/farmacologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Apoptose/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Pessoa de Meia-Idade , Membranas Mitocondriais/metabolismo , Permeabilidade , Inibidores de Proteassoma , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Células Tumorais Cultivadas/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismoRESUMO
3,6-Dimethyl-1,2,4,5-tetrazine-1,4-dicarboxamide derivatives were synthesized, and their structures were confirmed by single-crystal X-ray diffraction. This reaction yields the 1,4-dicarboxamide derivatives rather than the 1,2-dicarboxamide derivatives. Their in vitro antitumor activities were evaluated against SGC-7901, HO-8910, MCF-7, and A-549 cells. The results showed several compounds to be endowed with cytotoxicity in the low micromolar range. One compound (IC(50) =0.57 µM) was further evaluated in vivo against an A-549 xenograft in BALB/cA nude mice; it effected 76.4% inhibition of tumor weight through intraperitoneal (i.p.) administration of 40 mgkg(-1) body weight. Moreover, its acute toxicity was evaluated, and the i.p. LD(50) value was 325 mgkg(-1) in mice.
Assuntos
Amidas/química , Antineoplásicos/síntese química , Compostos Heterocíclicos com 3 Anéis/química , Amidas/uso terapêutico , Amidas/toxicidade , Animais , Antineoplásicos/uso terapêutico , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Cristalografia por Raios X , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Camundongos , Camundongos Nus , Conformação Molecular , Relação Estrutura-Atividade , Transplante HeterólogoRESUMO
A series of novel compounds 7-43 were prepared via the condensation of enaminones 4a-h and the guanidines carbonate 6a-f. The structures of these newly synthesized compounds were confirmed by (1) H-NMR, MS, EA and IR. All the compounds were tested for their cytotoxic activity in vitro against human cancer cell lines including Ishikawa, A549, BEL-7404, SPC-A-01 and SGC-7901. Most of them showed moderate cytotoxic against the tested cell lines. Among them, the most potent compounds 9 and 30 exhibited more efficient activity against Ishikawa, A549.
Assuntos
Antineoplásicos/síntese química , Desenho de Fármacos , Pirimidinas/síntese química , Tiazóis/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Pirimidinas/química , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologiaRESUMO
In the title compound, C(23)H(23)N(5)S, the thia-zole ring and pyrimidine ring are almost coplanar, making a dihedral angle of 4.02â (9)°. in the crystal, weak inter-molecular N-Hâ¯N inter-actions link pairs of molecules into centrosymmetric dimers.
RESUMO
In the title compound, C(22)H(19)Cl(2)N(5)S, the thia-zole and pyrimidine rings are almost co-planar, making a dihedral angle of 6.48â (7)°. In the crystal, intermolecular N-Hâ¯N hydrogen bonds link pairs of molecules into centrosymmetric dimers..
RESUMO
The asymmetric unit of the title compound, C(23)H(23)N(5)OS, contains two independent mol-ecules. In one mol-ecule, the thia-zole and pyrimidine rings are almost co-planar, making a dihedral angle of 2.48â (8)°. In the other mol-ecule, the corresponding dihedral angle is 12.82â (8)°. The crystal structure is stabilized by weak inter-molecular N-Hâ¯N and C-Hâ¯O inter-actions that extend along the b axis.
RESUMO
Thirty-seven (E)-1-(4-methyl-2-arylaminothiazol-5-yl)-3-arylprop-2-en-1-ones were synthesized via Claisen-Schmidt condensation of 1-(4-methyl-2-(arylamino)thiazol-5-yl)ethanone with the corresponding arylaldehydes. All these thiazolyl-chalcones were characterized and evaluated by MTT assay on human cancer cell lines BGC-823, PC-3, NCI-H460, BEL-7402 in vitro. Compounds 5, 8, 26, 37 and 41 are effective against cancer cell lines with IC(50)s below 10 µM. The antitumor activity in ICR mice bearing sarcoma 180 tumors indicates compounds 10 and 41 have moderate in vivo activity with 22-25% tumor-weight inhibition.
Assuntos
Chalconas/síntese química , Chalconas/farmacologia , Tiazóis/química , Animais , Linhagem Celular Tumoral , Chalconas/química , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Endogâmicos ICRRESUMO
alpha-Lipoic acid derivatives were synthesized and evaluated for their in vitro anticancer activities against NCI-460, HO-8910, KB, BEL-7402, and PC-3 cell lines. The results, for most compounds exhibited dose-dependent inhibitory property and several compounds had good inhibitions at the dose of 100 microg/mL. Compound 17 m was further selected for in vivo evaluation against S180 xenograft in ICR mice, which had 24.7% tumor-weight inhibition through intragastric administration of 200mg/kg of body weight. Moreover, the LD(50) in mice for 17 m through ig exceeded 1000 mg/kg of body weight.
Assuntos
Antineoplásicos/síntese química , Ácido Tióctico/análogos & derivados , Ácido Tióctico/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Relação Estrutura-Atividade , Ácido Tióctico/síntese química , Ácido Tióctico/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: To study whether N, N'-di-(m-methylphenyi)-3,6-dimethyl-1,4-dihydro-1,2,4,5-tetrazine-1,4-dicarboamide (ZGDHu-1) inhibits proliferation and induces apoptosis in human lung carcinoma cell line EBC-1 cells and its molecular mechanism. METHODS: Different concentrations of ZGDHu-1 and different times of culture were used to treat EBC-1 cells in vitro. The inhibition of proliferation was measured by BrdU-ELISA. Cell apoptosis was detected by Annexin V/PI staining and cellular DNA fragmentation ELISA. Phosphorylated p38MAPK and STAT3 were examined by flow cytometry. The protein expressions of bcl-2, bax, p53, Fas, and caspase-3 were detected by Western blot analysis. RESULTS: ZGDHu-1 inhibited EBC-1 cell proliferation within a certain range of treating times and does, with a 24 h IC(50) of (295 ± 25) ng/ml, 48 h of (112 ± 8) ng/ml and 72 h of (23 ± 2) ng/ml. The EBC-1 cell apoptosis was confirmed by Annexin V/PI labeling and cellular DNA fragmentation ELISA in a dose-related manner. When EBC-1 cells were treated with 50, 200, and 500 ng/ml ZGDHu-1 for 48 h, the expression rates of phosphor-p38MAPK protein were 67.4%, 88.2%, 91.1%, respectively, and that of the control was 10.6%. That of STAT3 protein were 56.5%, 43.6% and 34.6%, respectively, and that of the control was 89.1%. The expression of bax, p53 and Fas protein was significantly increased, that of bcl-2 was not changed, and that of caspase-3 was significantly decreased by the ZGDHu-1 treatment. CONCLUSION: ZGDHu-1 can inhibit proliferation and induce apoptosis in EBC-1 cells. The mitochondrial pathway mediated by Fas may be one of its mechanisms. The apoptosis of EBC-1 cells may associate with up-regulation of phosphor-p38MAPK and down-regulation of phosphor-STAT3 in the cells.
Assuntos
Apoptose/efeitos dos fármacos , Compostos Heterocíclicos com 1 Anel/farmacologia , Neoplasias Pulmonares/patologia , Fator de Transcrição STAT3/metabolismo , Receptor fas/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Fragmentação do DNA , Compostos Heterocíclicos com 1 Anel/administração & dosagem , Humanos , Neoplasias Pulmonares/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2/metabolismoRESUMO
In the title mol-ecule, C(17)H(14)O(4), the C atom of the carboxyl group deviates by 1.221â (3)â Å from the plane [maximum deviation = 0.0122(2)â Å] of the tricycic ring system. In the crystal structure, inter-molecular O-Hâ¯O hydrogen bonds link the mol-ecules into centrosymmetric dimers, and π-π inter-actions [centroid-centroid distances = 3.491â (3), 3.591â (3), 3.639â (3) and 3.735â (3)â Å] link these dimers into layers parallel to the ac plane. Weak inter-molecular C-Hâ¯O inter-actions further consolidate the crystal packing.
RESUMO
To discover the new medicinal activity, the structure of diflunisal has been modified. Forty amide derivatives of diflunisal were synthesized starting from diflunisal in three steps. Their inhibition growth rate of human lung cancer cell (A549) and human endometrial adenocarcinoma cell (Ishikawa) in vitro was evaluated. The preliminary assay results showed that compounds 6j, 7o and 8c exhibited good anti-tumor activities and excellent selectivity for the Ishikawa cell, may be potential anti-tumor agents.
Assuntos
Amidas/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Química Farmacêutica/métodos , Diflunisal/análogos & derivados , Diflunisal/síntese química , Neoplasias/tratamento farmacológico , Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X/métodos , Diflunisal/farmacologia , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Estrutura MolecularRESUMO
A series of caffeic acid amide derivatives 2-cyano-(3-substituted phenyl)acrylamides were synthesized via Knoevenogal condensation of substituted benzaldehydes with cyanoacetamides. The structure of compound 1f was determined as E-isomer by X-ray diffractive analysis. The biological screening tests in vitro showed that compound 1b has obvious inhibitory activities against human gastric carcinoma cell line BGC-823, human nasopharyngeal carcinoma cell line KB and human hepatoma cell line BEL-7402 with IC(50) values of 5.6 microg/mL, 13.1 microg/mL and 12.5 microg/mL, respectively. Some preliminary structure-activity relationships (SAR) were also proposed which may provide a direction for further study.
Assuntos
Acrilamidas/síntese química , Acrilamidas/farmacologia , Ácidos Cafeicos/química , Nitrilas/síntese química , Nitrilas/farmacologia , Acrilamidas/química , Linhagem Celular Tumoral , Cristalografia por Raios X , Humanos , Concentração Inibidora 50 , Nitrilas/química , Relação Estrutura-AtividadeRESUMO
To improve the medicinal activity, the structure of diflunisal has been modified. Twenty-one amide derivatives of diflunisal were synthesized starting from diflunisal in three steps with total yields from 72% to 89%. All compounds were identified by (1)H NMR, MS, and elemental analysis. The anti-inflammatory and analgesic activities for 19 compounds were evaluated. It was found that 5m possesses an excellent anti-inflammatory activity and a good analgesic activity, maybe a potential anti-inflammatory agent.
Assuntos
Amidas/química , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Diflunisal/síntese química , Diflunisal/farmacologia , Anti-Inflamatórios/química , Diflunisal/química , Avaliação Pré-Clínica de Medicamentos , Espectroscopia de Ressonância Magnética , Espectrometria de MassasRESUMO
The title compound, C(12)H(10)N(2)O(6), was synthesized via a Knoevenagel condensation and crystallized from ethanol. In the crystal, strong classical inter-molecular O-Hâ¯O hydrogen bonds and weak C-Hâ¯N contacts link the mol-ecules into ribbons extending along [010]. Intra-molecular O-Hâ¯O and C-Hâ¯N contacts support the planar conformation of the mol-ecules (mean deivation 0.0270â Å).
RESUMO
In the title compound, C(7)H(6)Cl(2)N(2)S, the benzene ring and the mean plane of the thio-urea fragment [-N-C(=S)-N] make a dihedral angle of 66.77â (3)°. Inter-molecular N-Hâ¯S and N-Hâ¯Cl hydrogen bonds link the mol-ecules into a three-dimensional network.
RESUMO
Forty caffeate analogues were synthesized via a convenient method starting from vanillin with moderate to good yields. The testing of biological activity of these compounds against HIV-1 integrase indicates that four compounds: bornyl caffeate, bornyl 2-nitrocaffeate, 5-nitrocaffeic acid and 5-nitrocaffeic acid phenethyl ester (5-nitroCAPE) possess a good HIV integrase inhibitory activity, IC(50) 19.9, 26.8, 25.0 and 13.5 microM , respectively. Twelve caffeate analogues were tested by MTT assay on growth of human hepatocellular carcinoma BEL-7404, human breast MCF-7 adenocarcinoma, human lung A549 adenocarcinoma and human gastric cancer BCG823 cell lines, respectively. And the best result is IC(50) 5.5 microM for CAPE against BEL-7404.