Huang Huaiyi, Zhang Pingyu, Chen Yu, Qiu Kangqiang, Jin Chengzhi, Ji Liangnian, Chao Hui
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, P. R. China.
Dalton Trans. 2016 Aug 16;45(33):13135-45. doi: 10.1039/c6dt01270a.
DNA binding and DNA transcription inhibition is regarded as a promising strategy for cancer chemotherapy. Herein, chloro terpyridyl Ru(ii) complexes, Ru(tpy)(N^N)Cl (Ru1, N^N = 2,2'-bipyridine; Ru2, N^N = 3-(pyrazin-2-yl)-as-triazino[5,6-f]acenaphthylene; Ru3, N^N = 3-(pyrazin-2-yl)-as-triazino[5,6-f]phenanthrene; Ru4, N^N = 3-(pyrazin-2-yl)-as-triazino[5,6-f]pyrene) were prepared as DNA intercalative and covalent binding anticancer agents. The chloro ligand hydrolysis slowly and the octanol and water partition coefficient of Ru2-Ru4 were between 0.6 and 1.2. MALDI-TOF mass, DNA gel electrophoresis confirmed covalent and intercalative DNA binding modes of Ru2-Ru4, while Ru1 can only bind DNA covalently. As a result, Ru2-Ru4 exhibited stronger DNA transcription inhibition activity, higher cell uptake efficiency and better anticancer activity than Ru1. Ru4 was the most toxic complex toward all cancer cells which inhibited DNA replication and transcription. AO/EB, Annexin V/PI, nuclear staining, JC-1 assays further confirmed that Ru2-Ru4 induced cancer cell death by an apoptosis mechanism.
DNA结合和DNA转录抑制被认为是一种很有前景的癌症化疗策略。在此，制备了氯代三联吡啶钌（II）配合物Ru(tpy)(N^N)Cl（Ru1，N^N = 2,2'-联吡啶；Ru2，N^N = 3-(吡嗪-2-基)-三氮唑并[5,6-f]苊烯；Ru3，N^N = 3-(吡嗪-2-基)-三氮唑并[5,6-f]菲；Ru4，N^N = 3-(吡嗪-2-基)-三氮唑并[5,6-f]芘）作为DNA插入和共价结合抗癌剂。氯配体水解缓慢，Ru2 - Ru4的正辛醇/水分配系数在0.6至1.2之间。基质辅助激光解吸电离飞行时间质谱、DNA凝胶电泳证实了Ru2 - Ru4的共价和插入DNA结合模式，而Ru1只能与DNA共价结合。结果，Ru2 - Ru4比Ru1表现出更强的DNA转录抑制活性、更高的细胞摄取效率和更好的抗癌活性。Ru4对所有癌细胞毒性最大，可抑制DNA复制和转录。吖啶橙/溴化乙锭、膜联蛋白V/碘化丙啶、细胞核染色、JC-1检测进一步证实Ru2 - Ru4通过凋亡机制诱导癌细胞死亡。
