Novel cyclometalated Ru(II) complexes containing isoquinoline ligands: Synthesis, characterization, cellular uptake and in vitro cytotoxicity
Novel cyclometalated Ru(II) complexes containing isoquinoline ligands: Synthesis, characterization, cellular uptake and in vitro cytotoxicity
复制标题
含有异喹啉配体的新型环金属化钌 (II) 配合物：合成、表征、细胞摄取和体外细胞毒性
DOI：
10.1016/j.ejmech.2020.112562
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发表时间：
2020-10-01
影响因子：
6.7
通讯作者：
Wang, Tao
中科院分区：
文献类型：
--
作者：
Chen, Jincan;Wang, Jie;Wang, Tao
合成了两种新型的含异喹啉配体的环化钌配合物[Ru（bpy）（2）（1-Ph-IQ）]（PF 6），（bpy = 2，2 '-联吡啶; 1-Ph-IQ = 1-苯基异喹啉; RuIQ-1）和[Ru（phen）（2）（1-Ph-IQ）]（PF 6）（phen = 1，10-菲咯啉; RuIQ-2）显示出对NCI-H460、A549、HeLa和MCF-7细胞系的高细胞毒活性。值得注意的是，它们都表现出比临床顺铂和两种结构相似的Ru（II）-异喹啉络合物[Ru（bpy）（2）（1-Py-IQ）]（PF 6）（2）（Ru 3）和[Ru（phen）（2）（1-Py-IQ）]（PF 6）（2）（Ru 4）（1-Py-IQ = 1-吡啶-2-基）的IC 50值低一个数量级。细胞摄取和细胞内定位结果表明，两种环化钌配合物主要通过内吞途径进入NCI-H460细胞，并优先分布于细胞核。进一步研究RuIQ-1和RuIQ-2诱导细胞凋亡的机制发现，RuIQ-1和RuIQ-2可通过调控细胞周期相关蛋白，导致S、G2/M双周期阻滞。这两种复合物还可降低线粒体膜电位（MMP），促进细胞内ROS的产生，引发DNA损伤，进而导致凋亡介导的细胞死亡。更重要的是，RuIQ-2在体外对正常HBE细胞和体内对斑马鱼胚胎都表现出低毒性。因此，开发的配合物具有很大的潜力，可开发为有效和低毒的癌症治疗的新疗法。(C)2020 Elsevier Masson SAS。All rights reserved.
Two novel cyclometalated Ru(II) complexes containing isoquinoline ligand, [Ru(bpy)(2)(1-Ph-IQ)](PF6), (bpy = 2,2'-bipyridine; 1-Ph-IQ = 1-phenylisoquinoline; RuIQ-1) and [Ru(phen)(2)(1-Ph-IQ)](PF6) (phen = 1,10-phenanthroline; RuIQ-2) were found to show high cytotoxic activity against NCI-H460, A549, HeLa and MCF-7 cell lines. Notably, both of them exhibited IC50 values that were an order of magnitude lower than those of clinical cisplatin and two structurally similar Ru(II)-isoquinoline complexes [Ru(bpy)(2)(1-PY-IQ)I(PF6)(2) (Ru3) and [Ru(phen)(2)(1 Py-IQ)](PF6)(2) (Ru4) (1-Py-IQ = 1-pyridine-2-yl). The cellular uptake and intracellular localization displayed that the two cyclometalated Ru(II) complexes entered NCI-H460 cancer cells dominantly via endocytosis pathway, and preferentially distributed in the nucleus. Further investigations on the apoptosis-inducing mechanisms of RuIQ-1 and RuIQ-2 revealed that the two complexes could cause S, G2/M double cycle arrest by regulating cell cycle related proteins. The two complexes also could reduce the mitochondrial membrane potential (MMP), promote the generation of intracellular ROS and trigger DNA damage, and then lead to apoptosis-mediated cell death. More importantly, RuIQ-2 exhibits low toxicity both towards normal HBE cells in vitro and zebrafish embryos in vivo. Accordingly, the developed complexes hold great potential to be developed as novel therapeutics for effective and low-toxic cancer treatment. (C) 2020 Elsevier Masson SAS. All rights reserved.