JNK1 is a drug target for the treatment of type 2 diabetes,and it plays a key mediator role in metabolic disorders.In this paper,holographic quantitative structure-activity relationship(HQSAR)technology and Topomer co...JNK1 is a drug target for the treatment of type 2 diabetes,and it plays a key mediator role in metabolic disorders.In this paper,holographic quantitative structure-activity relationship(HQSAR)technology and Topomer comparative molecular field analysis(Topomer CoMFA)technology are used to analyze the quantitative structure-activity relationship(QSAR)of 39 isoquinolone derivatives.The cross validation correlation coefficient(q^(2))is 0.696(Topomer CoMFA)and 0.826(HQSAR),and the non-cross validation correlation coefficient(r^(2))is 0.935(Topomer CoMFA)and 0.987(HQSAR).The results showed that the models have good stability and predictive ability.The Topomer search module was applied to define high contribution fragments in the ZINC database,designing 20 new isoquinolone compounds with theoretically high inhibitory activity.The molecular docking was carried out to explore the interaction between the ligand and target JNK1 protein.This study can provide a theoretical basis for the design of new JNK1 inhibitors.展开更多
A series of isoquinolonic acid derivatives（4a-4o） was synthesized via one-pot synthesis for their anti-tumor activity. The structures of all the targeted compounds were confirmed by IH nuclear magnetic resonance （I...A series of isoquinolonic acid derivatives（4a-4o） was synthesized via one-pot synthesis for their anti-tumor activity. The structures of all the targeted compounds were confirmed by IH nuclear magnetic resonance （IH NMR） spectrometry and mass spectrometry（MS）. The anti-tumor activities of compounds 4a-4o against MG63（human osteosarcoma cells） and B16-F10（mouse melanoma cells） were examined. To evaluate the antitumor effect of the as-synthesized compounds, we compared the half maximal inhibitory concentration（1C50） of compounds 4a--4o to that of camptothecin（CPT） which appeared to be active against a broad range of human cancers. Among all the compounds, compound 41 shows the most potent biological activity against MG63 cells[IC50=（2.16i0.26） μmol/L] and B16-F10 cells[IC50=（6.95±0.24）μmol/L], thus providing useful information for the antitumor activity and potential practical use of isoquinolonic acid compounds. In addition, we screened out an efficient compound（41） that shows potential inhibit activity against Topoisomerase 1（Topo 1） by docking simulation.展开更多
基金This work was supported by the National Natural Science Funds of China(21475081)Innovation Supporting Plan of Shaanxi Province-Innovation Research Team(No.2018TD-015)the Graduate Innovation Fund of Shaanxi University of Science and Technology.
文摘JNK1 is a drug target for the treatment of type 2 diabetes,and it plays a key mediator role in metabolic disorders.In this paper,holographic quantitative structure-activity relationship(HQSAR)technology and Topomer comparative molecular field analysis(Topomer CoMFA)technology are used to analyze the quantitative structure-activity relationship(QSAR)of 39 isoquinolone derivatives.The cross validation correlation coefficient(q^(2))is 0.696(Topomer CoMFA)and 0.826(HQSAR),and the non-cross validation correlation coefficient(r^(2))is 0.935(Topomer CoMFA)and 0.987(HQSAR).The results showed that the models have good stability and predictive ability.The Topomer search module was applied to define high contribution fragments in the ZINC database,designing 20 new isoquinolone compounds with theoretically high inhibitory activity.The molecular docking was carried out to explore the interaction between the ligand and target JNK1 protein.This study can provide a theoretical basis for the design of new JNK1 inhibitors.
基金the National Natural Science Foundation of China，the Program for Changjiang Scholars and Innovative Research Team in University,China，the Fundamental Research Funds for the Central Universities,China，the Natural Science Foundations of Jiangsu Province,China
文摘A series of isoquinolonic acid derivatives（4a-4o） was synthesized via one-pot synthesis for their anti-tumor activity. The structures of all the targeted compounds were confirmed by IH nuclear magnetic resonance （IH NMR） spectrometry and mass spectrometry（MS）. The anti-tumor activities of compounds 4a-4o against MG63（human osteosarcoma cells） and B16-F10（mouse melanoma cells） were examined. To evaluate the antitumor effect of the as-synthesized compounds, we compared the half maximal inhibitory concentration（1C50） of compounds 4a--4o to that of camptothecin（CPT） which appeared to be active against a broad range of human cancers. Among all the compounds, compound 41 shows the most potent biological activity against MG63 cells[IC50=（2.16i0.26） μmol/L] and B16-F10 cells[IC50=（6.95±0.24）μmol/L], thus providing useful information for the antitumor activity and potential practical use of isoquinolonic acid compounds. In addition, we screened out an efficient compound（41） that shows potential inhibit activity against Topoisomerase 1（Topo 1） by docking simulation.
