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目的设计并合成6,7-亚甲二氧基-3-芳基-2H,4H-苯并噻嗪衍生物,测定其体外抗肿瘤活性及对微管蛋白聚合和细胞周期的影响。方法以鬼臼毒素和ABT-751结构为基础,采用基于片段的药物设计方法合成目标化合物,以MTT法测试目标化合物体外对正常细胞及肿瘤细胞的抑制活性,以340 nm处吸光度值的变化确定其对微管蛋白的抑制率,通过流式细胞术检测其对实验肿瘤细胞周期的影响。结果合成了6种目标物,采用IR、MS、1H-NMR及元素分析对其结构进行表征,得到了活性测试数据。结论 6种目标化合物对人正常VEC细胞的毒性均低于阳性对照鬼臼毒素,3e和3f对A-549细胞,3a、3d、3e、3f对HCT-116细胞体外抑制活性均优于阳性对照鬼臼毒素。在30μmol·L-1水平上,3e和3f对微管蛋白聚合具有较好的抑制作用。随浓度的增大,3e阻滞BGC-823细胞以及3f阻滞A-549、BGC-823和HCT116的细胞周期停留在G2/M期的比例也在升高。
OBJECTIVE To design and synthesize 6,7-methylenedioxy-3-aryl-2H, 4H-benzothiazine derivatives and determine their in vitro anti-tumor activity and their effects on tubulin polymerization and cell cycle. Methods Based on the structure of podophyllotoxin and ABT-751, a fragment-based drug design method was used to synthesize the target compound. The inhibitory activity of the target compound on normal cells and tumor cells was tested by MTT assay, and the change of absorbance value at 340 nm Its inhibitory rate on tubulin was examined by flow cytometry on the experimental tumor cell cycle. Results Six target compounds were synthesized. Their structures were characterized by IR, MS, 1H-NMR and elemental analysis, and the activity test data were obtained. CONCLUSION: The cytotoxic activity of 6 target compounds to human normal VEC cells is lower than that of positive control podophyllotoxin. The inhibitory activity of 3e and 3f to A-549 cells in vitro is better than that of positive control in HCT-116 cells (3a, 3d, 3e and 3f) Podophyllotoxin. At 30μmol·L-1 level, 3e and 3f had good inhibitory effect on tubulin polymerization. With the increase of concentration, the proportion of 3e-arresting BGC-823 cells and 3f-arresting A-549, BGC-823 and HCT116 cell cycle in G2 / M phase also increased.