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Eur J Med Chem ; 183: 111679, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31541870


Anti-tubulin polymerization agents can disrupt tumor-vascular to exhibit anti-cancer potency. In this study, a series of substituted (2-(phenylamino)thieno[3,2-d]pyrimidin-4-yl)(3,4,5-trimethoxyphenyl)methanone analogues were designed and synthesized as anti-tubulin polymerization agents that interact with colchicine binding site. The anti-proliferative assay indicated that most of the target compounds displayed moderate to high potencies towards five tumor cell lines. The structure-activity relationship of these analogues was summarized. The most potent compound 14 was selected to assay its inhibition on the tubulin polymerization. 14 displayed potent inhibition against tubulin polymerization with an IC50 value of 4.1 ±â€¯0.1 µM. The colchicine competition assay demonstrated that 14 inhibited tubulin polymerization by binding to the colchicine-binding site of tubulin. The molecular modeling study elucidated the binding mode of 14 in the colchicine binding site. The result of confocal immunofluorescent study proved that 14 can quickly disrupt the microtubules of Hela cells in a concentration dependent manner. Some experiments at cellular level were conducted to investigate the effects of 14 on cellular morphology, cell colony formation, cell cycle distribution, cell apoptosis and mitochondrial changes. The results demonstrated that 14 is a potent anti-tubulin agent with strong concentration dependent effect of inhibition of colony formation, induction of G2/M arrest and induction of apoptosis through mitochondrial pathway.

Antineoplásicos/síntese química , Pirimidinas/síntese química , Moduladores de Tubulina/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colchicina/metabolismo , Desenho de Drogas , Humanos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Moduladores de Tubulina/farmacologia
PLoS One ; 12(7): e0181983, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28759617


This study aims to investigate the flow and fracture behavior of aluminum alloy 6082-T6 (AA6082-T6) at different strain rates and triaxialities. Two groups of Charpy impact tests were carried out to further investigate its dynamic impact fracture property. A series of tensile tests and numerical simulations based on finite element analysis (FEA) were performed. Experimental data on smooth specimens under various strain rates ranging from 0.0001~3400 s-1 shows that AA6082-T6 is rather insensitive to strain rates in general. However, clear rate sensitivity was observed in the range of 0.001~1 s-1 while such a characteristic is counteracted by the adiabatic heating of specimens under high strain rates. A Johnson-Cook constitutive model was proposed based on tensile tests at different strain rates. In this study, the average stress triaxiality and equivalent plastic strain at facture obtained from numerical simulations were used for the calibration of J-C fracture model. Both of the J-C constitutive model and fracture model were employed in numerical simulations and the results was compared with experimental results. The calibrated J-C fracture model exhibits higher accuracy than the J-C fracture model obtained by the common method in predicting the fracture behavior of AA6082-T6. Finally, the Scanning Electron Microscope (SEM) of fractured specimens with different initial stress triaxialities were analyzed. The magnified fractographs indicate that high initial stress triaxiality likely results in dimple fracture.

Ligas/química , Alumínio/química , Teste de Materiais/métodos , Resistência à Tração , Teste de Materiais/instrumentação