噻唑并三嗪类化合物的合成及其基于U2OS-EGFP细胞的抗肿瘤活性

Synthesis and antitumor activity based on U2OS-EGFP cells of 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives

目的探讨7H-噻唑并[3,2-b]-1,2,4-三嗪类化合物的体外肿瘤细胞增殖抑制活性,及初步的构效关系和作用机理。方法以3,4-二氢-6-芳基-3-硫代-1,2,4-三嗪-5(2H)-酮为原料,经环合反应、Williamson反应,合成7H-噻唑并[3,2-b]-1,2,4-三嗪类化合物,考察目标化合物体外肿瘤细胞增殖抑制作用。结果与结论合成了10个7H-噻唑并[3,2-b]-1,2,4-三嗪类化合物,经MS、1H-NMR确证结构。体外抗肿瘤活性研究显示,有4个化合物在50μmol·L^(-1)时对骨肉瘤细胞U2OS-EGFP抑制率高于50%。其中,活性最好的化合物4 d对U2OS-EGFP细胞抑制活性的IC50值为9.824μmol·L^(-1)。分子模拟结果显示,这类化合物作用于ERK1/2,应是一种ERK1/2抑制剂。

Objective To explore the multiplication inhibitory activities of the tumor cells,the preliminary structure-activity relationship and action mechanism of 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives.Methods 7H-Thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives ere synthesized taking 3,4-dihydro-6-aryl-3-thioxo-1,2,4-triazin-5（ 2H）-one derivatives as starting materials,follow ed by cyclization reaction,and Williamson reaction. The multiplication inhibitory activities of the tumor cells of the target compounds ere tested. Results and Conclusions Ten 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives ere synthesized,and the structures of the target compounds ere characterized by MS and1H-NMR. The screening results of anti-tumor activity show ed that the inhibitory ratio values of U2OS-EGFP cell of four compounds ere greater than 50% at 50 μmol·L^-1. Compound 4d exhibited the most potent inhibitory activity of U2OS-EGFP cell,its IC50 value as 9. 824 μmol·L^-1. The results of the molecular docking show ed that ERK1 /2 ere the active sites of the target compounds,which probably ere a new kind of ERK1 /2 inhibitors.