有机化学 ›› 2021, Vol. 41 ›› Issue (7): 2723-2734.DOI: 10.6023/cjoc202012047 上一篇    下一篇

研究论文

新型有机硫(硒)替加氟衍生物的合成及抗肿瘤活性研究

李宁波a,b,c,*(), 续立a, 马榕a, 范琪a, 李波b, 乔洁a,b, 郭睿a,c,*(), 许新华d   

  1. a 山西医科大学生物化学与分子生物学教研室 山西太原 030001
    b 山西医科大学医用化学教研室 山西太原 030001
    c 山西医科大学细胞生理学教育部重点实验室 山西太原 030001
    d 湖南大学化学化工学院 长沙 410082
  • 收稿日期:2020-12-28 修回日期:2021-03-30 发布日期:2021-04-16
  • 通讯作者: 李宁波, 郭睿
  • 基金资助:
    国家自然科学基金(21802093); 山西省高等学校科技创新(2019L0408); 山西医科大学博士启动基金(03201501)

Synthesis and Antitumor Activities of Novel Organic Sulfur (Selenium) Tegafur Derivatives

Ningbo Lia,b,c(), Li Xua, Rong Maa, Qi Fana, Bo Lib, Jie Qiaoa,b, Rui Guoa,c(), Xinhua Xud   

  1. a Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, Shanxi 030001
    b Department of Chemistry, Shanxi Medical University, Taiyuan, Shanxi 030001
    c Key Laboratory of Cellular Physiology, Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi 030001
    d College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082
  • Received:2020-12-28 Revised:2021-03-30 Published:2021-04-16
  • Contact: Ningbo Li, Rui Guo
  • Supported by:
    National Natural Science Foundation of China(21802093); Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi Province(2019L0408); PhD Start-up Foundation of Shanxi Medical University(03201501)

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