Qu Hong-En, Huang Ri-Zhen, Yao Gui-Yang, Li Jiu-Ling, Ye Man-Yi, Wang Heng-Shan, Liu Liangxian
State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, PR China.
Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China.
Eur J Med Chem. 2015 May 5;95:400-15. doi: 10.1016/j.ejmech.2015.03.058. Epub 2015 Mar 27.
In an effort to develop potent anti-cancer chemopreventive agents, a novel series of bisindole derivatives bearing oxime moiety were synthesized. Structures of all compounds were characterized by NMR and HRMS. Anti-proliferative activities for all of these compounds were investigated by the method of MTT assay on 7 human cancer lines and the normal cell lines (HUVEC). Most of them showed a noteworthy anti-cancer activity in vitro, the half maximal inhibitory concentration (IC50) value is 4.31 μM of 4e against T24. The results from Hoechst 33258 and acridine orange/propidium iodide staining as well as annexinV-FITC assays provided evidence for an apoptotic cell death. The further mechanisms of compound 4e-induced apoptosis in T24 cells demonstrated that compound 4e induced the productions of ROS, and altered anti- and pro-apoptotic proteins, leading to mitochondrial dysfunction and activations of caspase-9 and caspase-3 for causing cell apoptosis. Moreover, the cell cycle analysis and western-blot analysis indicated that compound 4e effectively arrested T24 cells in G1 stage and possibly has an effect on cell cycle regulatory proteins particularly cyclin D1.
为了开发有效的抗癌化学预防剂，合成了一系列新型的带有肟部分的双吲哚衍生物。所有化合物的结构均通过核磁共振（NMR）和高分辨质谱（HRMS）进行了表征。采用MTT法对7种人类癌细胞系和正常细胞系（人脐静脉内皮细胞，HUVEC）研究了所有这些化合物的抗增殖活性。它们中的大多数在体外显示出显著的抗癌活性，化合物4e对T24细胞的半数最大抑制浓度（IC50）值为4.31 μM。Hoechst 33258和吖啶橙/碘化丙啶染色以及膜联蛋白V-异硫氰酸荧光素（annexinV-FITC）检测结果为凋亡性细胞死亡提供了证据。化合物4e诱导T24细胞凋亡的进一步机制表明，化合物4e诱导了活性氧（ROS）的产生，并改变了抗凋亡和促凋亡蛋白，导致线粒体功能障碍以及半胱天冬酶-9（caspase-9）和半胱天冬酶-3（caspase-3）的激活，从而引起细胞凋亡。此外，细胞周期分析和蛋白质免疫印迹分析表明，化合物4e有效地将T24细胞阻滞在G1期，并且可能对细胞周期调节蛋白尤其是细胞周期蛋白D1有影响。
