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Synthesis, characterization, cellular uptake and apoptosis-inducing properties of two highly cytotoxic cyclometalated ruthenium(II) β-carboline complexes
European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2017-09-06 , DOI: 10.1016/j.ejmech.2017.09.007
Jincan Chen , Fa Peng , Yao Zhang , Baojun Li , Ji She , Xinming Jie , Zhilin Zou , Man Chen , Lanmei Chen

Two new cyclometalated Ru(II) complexes of the general formula [Ru(N-N)2(1-Ph-βC)](PF6), where N–N = 4,4′-dimethyl-2,2′-bipyridine (dmb, Ru1), 2,2′-bipyridine (bpy, Ru2), and 1-Ph-βC (1-phenyl-9H-pyrido[3,4-b]indole) is a β-carboline alkaloids derivatives, have been synthesized and characterized. The in vitro cytotoxicities, cellular uptake and localization, cell cycle arrest and apoptosis-inducing mechanisms of these complexes have been extensively explored by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, inductively coupled plasma mass spectrometry (ICP-MS), flow cytometry, comet assay, inverted fluorescence microscope as well as western blotting experimental techniques. Notably, Ru1 and Ru2 exhibit potent antiproliferative activities against selected human cancer cell lines with IC50 values lower than those of cisplatin and other non-cyclometalated Ru(II) β-carboline complexes. The cellular uptake and localization exhibit that these complexes can accumulate in the cell nuclei. Further antitumor mechanism studies show that Ru1 and Ru2 can cause cell cycle arrest in the G0/G1 phase by regulating cell cycle relative proteins and induce apoptosis through mitochondrial dysfunction, reactive oxygen species (ROS) accumulation and ROS-mediated DNA damage.



中文翻译:

两种高度细胞毒性的环金属化钌(II)β-咔啉配合物的合成,表征,细胞摄取和诱导细胞凋亡的特性

两种新的通式为[Ru(NN)2(1-Ph-βC)](PF 6)的环金属化Ru(II)络合物,其中N–N = 4,4'-二甲基-2,2'-联吡啶( dmb,Ru1),2,2'-联吡啶(bpy,Ru2)和1-Ph-βC(1-苯基-9 H-吡啶[3,4- b[吲哚]是β-咔啉生物碱的衍生物,已经合成并表征。这些配合物的体外细胞毒性,细胞摄取和定位,细胞周期阻滞和凋亡诱导机制已通过3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴化物(MTT)测定法进行了广泛探索。 ,电感耦合等离子体质谱(ICP-MS),流式细胞仪,彗星分析,倒置荧光显微镜以及蛋白质印迹实验技术。值得注意的是,Ru1Ru2对具有IC 50的选定人类癌细胞系表现出有效的抗增殖活性的值低于顺铂和其他非环金属化的Ru(II)β-咔啉配合物的值。细胞摄取和定位表明这些复合物可以在细胞核中积累。进一步的抗肿瘤机制研究表明,Ru1Ru2可以通过调节细胞周期相关蛋白而导致细胞周期停滞在G0 / G1期,并通过线粒体功能障碍,活性氧(ROS)积累和ROS介导的DNA损伤诱导细胞凋亡。

更新日期:2017-09-06
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