Milutinović Milan M, Rilak Ana, Bratsos Ioannis, Klisurić Olivera, Vraneš Milan, Gligorijević Nevenka, Radulović Siniša, Bugarčić Živadin D
Faculty of Science, University of Kragujevac, R. Domanovića 12, P. O. Box 60, 34000 Kragujevac, Serbia.
Faculty of Science, University of Kragujevac, R. Domanovića 12, P. O. Box 60, 34000 Kragujevac, Serbia.
J Inorg Biochem. 2017 Apr;169:1-12. doi: 10.1016/j.jinorgbio.2016.10.001. Epub 2016 Oct 14.
In this study, we have developed a series of new monofunctional Ru(II) complexes of the general formula mer-[Ru(Cl-Ph-tpy)(N-N)Cl]Cl in which Cl-Ph-tpy is 4'-(4-chlorophenyl)-2,2':6',2″-terpyridine, N-N is a bidentate chelating ligand (1,2-diaminoethane (en, 1), 1,2-diaminocyclohexane (dach, 2) or 2,2'-bipyridine (bpy, 3)). All complexes were fully characterized by elemental analysis and spectroscopic techniques (IR, UV-Vis, 1D and 2D NMR). Their chemical behavior in aqueous solution was studied by UV-Vis and NMR spectroscopy showing that all compounds are relatively labile leading to the formation of the corresponding aqua species 1aq-3aq. Their DNA binding ability was evaluated by UV-Vis spectroscopy, fluorescence quenching measurements and viscosity measurements. Competitive studies with ethidium bromide (EB) showed that the complexes can displace DNA-bound EB, suggesting strong competition with EB (K=1.1-2.7×10M). These experiments show that the ruthenium complexes interact with DNA via intercalation. The complexes bind to serum protein albumin displaying relatively high binding constants (K=10-10M). Compound 3 displayed from high to moderate cytotoxicity against two cancer cell lines HeLa and A549 (with ICca. 12.7μM and 53.8μM, respectively), while complexes 1 and 2 showed only moderate cytotoxicity (with ICca. 84.8μM and 96.3μM, respectively) against HeLa cells. The cell cycle analysis (by flow cytometry) of HeLa and A549 cells treated with complex 3 shows minor changes on the cell cycle phase distribution.
在本研究中，我们合成了一系列通式为mer-[Ru(Cl-Ph-tpy)(N-N)Cl]Cl的新型单功能Ru(II)配合物，其中Cl-Ph-tpy为4'-(4-氯苯基)-2,2':6',2″-三联吡啶，N-N为双齿螯合配体（1,2-二氨基乙烷（乙二胺，1）、1,2-二氨基环己烷（环己二胺，2）或2,2'-联吡啶（bpy，3））。所有配合物均通过元素分析和光谱技术（红外光谱、紫外可见光谱、一维和二维核磁共振）进行了全面表征。通过紫外可见光谱和核磁共振光谱研究了它们在水溶液中的化学行为，结果表明所有化合物相对不稳定，会形成相应的水合物种1aq - 3aq。通过紫外可见光谱、荧光猝灭测量和粘度测量评估了它们与DNA的结合能力。与溴化乙锭（EB）的竞争研究表明，这些配合物可以取代与DNA结合的EB，表明与EB存在强烈竞争（K = 1.1 - 2.7×10M）。这些实验表明钌配合物通过插入作用与DNA相互作用。这些配合物与血清蛋白白蛋白结合，显示出相对较高的结合常数（K = 10 - 10M）。化合物3对两种癌细胞系HeLa和A549表现出从高到中等的细胞毒性（IC分别约为12.7μM和53.8μM），而配合物1和2对HeLa细胞仅表现出中等细胞毒性（IC分别约为84.8μM和96.3μM）。用配合物3处理的HeLa和A549细胞的细胞周期分析（通过流式细胞术）显示细胞周期阶段分布有微小变化。
