Synthesis, characterization, cellular uptake and apoptosis-inducing properties of two highly cytotoxic cyclometalated ruthenium(II) β-carboline complexes
Synthesis, characterization, cellular uptake and apoptosis-inducing properties of two highly cytotoxic cyclometalated ruthenium(II) β-carboline complexes
复制标题
两种高细胞毒性环金属化钌(II) β-咔啉配合物的合成、表征、细胞摄取和细胞凋亡诱导特性
DOI：
10.1016/j.ejmech.2017.09.007
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发表时间：
2017-11-10
影响因子：
6.7
通讯作者：
Chen, Lanmei
中科院分区：
文献类型：
--
作者：
Chen, Jincan;Peng, Fa;Chen, Lanmei
合成并表征了两个新的环化钌配合物[Ru（N-N）（2）（1-Ph-beta C）]（PF_6），其中N-N = 4，4 '-二甲基-2，2'-联吡啶（dmb，Ru_1），2，2 '-联吡啶（bpy，Ru_2），1-Ph-beta C（1-苯基-9H-吡啶并[3，4-B]吲哚）是一种β-咔啉生物碱衍生物。通过MTT法、ICP-MS法、流式细胞仪、彗星试验、倒置荧光显微镜和Western印迹等实验技术，对这些配合物的体外细胞毒性、细胞摄取和定位、细胞周期阻滞和诱导凋亡机制进行了深入研究。值得注意的是，Ru 1和Ru 2对选定的人类癌细胞系表现出有效的抗增殖活性，其IC 50值低于顺铂和其他非环化Ru（II）β-咔啉络合物的IC 50值。细胞摄取和定位表明，这些复合物可以积聚在细胞核中。进一步的抗肿瘤机制研究表明，Ru 1和Ru 2可通过调节细胞周期相关蛋白，使细胞周期阻滞在G 0/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。(C)2017 Elsevier Masson SAS。All rights reserved.
Two new cyclometalated Ru(II) complexes of the general formula [Ru(N-N)(2)(1-Ph-beta C)](PF6), where N-N = 4,4'-dimethyl-2,2'-bipyridine (dmb, Ru1), 2,2'-bipyridine (bpy, Ru2), and 1-Ph-beta C (1-phenyl-9H-pyrido[3,4-b]indole) is a beta-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) beta-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. (C) 2017 Elsevier Masson SAS. All rights reserved.