摘要/Abstract

以替加氟为原料, 与氯代烷基醇反应生成中间体N-羟烷基替加氟; 然后与对甲苯磺酰氯反应制得替加氟烷基磺酸酯;在双核钛全氟丁基磺酸配合物/锌粉催化体系下, 替加氟烷基磺酸酯与二芳基二硫(硒)醚反应,较高产率得到一系列新型芳基(N³-替加氟烷基)硫(硒)醚衍生物. 其结构通过¹H NMR,¹³H NMR和HRMS确认. 对目标化合物进行了关于结肠癌细胞HCT116和胃癌细胞SGC-7901的体外抗肿瘤活性测试. 结果表明, 绝大多数目标化合物比替加氟的抗肿瘤活性高. DAPI (4',6-diamidino-2-phenylindole)对HCT116细胞染色实验及流式细胞仪定量检测实验表明, 替加氟衍生物可通过诱导细胞凋亡而抑制细胞生长. 此外, 有机硫(硒)替加氟衍生物作用于正常人胚胎肾细胞HEK 293的毒性比替加氟低.
关键词: 替加氟, 二芳基二硫(硒)醚, 不对称硫(硒)醚, 抗肿瘤活性, 细胞凋亡
Tegafur, as a raw material, reacted with chloroalkyl alcohols to give the intermediateN-hydroxyalkyl tegafur, then which reacted withp-toluenesulfonyl chloride to obtain tegafluoroalkyl sulfonate. A series of novel aryl (N³-tegafluoroalkyl) thio- and seleno-ether derivatives were efficiently synthesized by the reaction of tegafluoroalkyl sulfonate with diaryl disulfides or diselenides under binuclear titanium(IV) salophen perfluorobutanesulfonate/zinc catalytic system. Their structures of the target products were confirmed by¹H NMR,¹³C NMR and HRMS. Their antitumor activities were evaluated by colorectal carcinoma HCT116 cells and gastric carcinoma SGC-7901 cells. The preliminary bioassay results showed that most target compounds had more antitumor activities than tegafur. Moreover, HCT116 cells staining experiments (DAPI) and quantitative determination by flow cytometry indicated that the growth inhibition was associated with the induction of apoptosis. In addition, organic sulfur (selenium) tegafur derivatives had lower toxicity than tegafur on human embryonic kidney HEK 293 cells.
Key words: tegafur, diaryl disulfides (diselenides), unsymmetrical sulfides (selenides), antitumor activity, apoptosis


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