Mononuclear And Binuclear Ruthenium(Ⅱ)Complexes: Synthesis, Characterization And Bioactivity Studies

Cancer is one of the most serious disease harm to human health. Chemotherapy is a primary method for cancer treatment, but chemotherapy drug have side effects and drug resistance. So seeking for effective, low toxic anti-cancer drug become the goal for researchers. Metal complexes, especially ruthenium complex attracted extensive attention since the finding of cisplatin. Compared to cisplatin, metal ruthenium complex have the advantages of low toxicity and effective anti-cancer. In this paper, some mononuclear and dinuclear ruthenium complexes were synthesized and characterized by element analysis,1H NMR, the infrared and mass spectrometry methods. The UV-vis absorption, fluorescence spectroscopy and electrochemical behavior were studied. The cytotoxicity in vitro was assayed by MTT array, the DNA-binding behaviors were investigated by fluorescence spectroscopy and agarose gel retardation assay. The apoptosis and cell cycle arrest were performed by flow cytometry. Specific works as follows:1. The first chapter introduced the development history of ruthenium complexes as anticancer drugs and research status. The basic theory and relative research methods of ruthenium complexes as anti-cancer drug were introduced. Finally, research significance and research contents were mentioned.2. In chapter 2, two monodentate ligands and two bidentate ligands were synthesized, and let them react with a variety of transition metal salts and cis-Ru(bpy)2Cl2·2H2O. Volatilization method, diffusion method and hydrothermal method were performed in order to obtain crystal, and finally got a ruthenium complex Ru1 and a copper complex Cu(L2)2 single crystals. The complexes were characterized by element analysis,1H NMR, the infrared and mass spectrometry methods, and confirmed by X-ray diffraction studies. The cytotoxic potential of the Ru1 was tested on AGS、 BGC823 and SGC7901 gastric cancer cells, Ru1 was cytotoxic to the three kinds of tumor cells. The mode of cell apoptosis was assessed by different morphological study (Hoechst staining, Acridine orange & ethidium bromide (AO & EB) staining) and flow cytometry assay. The Ru1 induced cell apoptosis in a dose- and time-dependent manner, and the mode of cell death was essentially apoptosis though necrosis was also noticed. Cell cycle analysis by flow cytometry indicated that the Ru1 caused cell cycle arrest and accumulated cells in S phase. The DNA binding properties with Rul was studied by gel electrophoresis.3. In chapter 3, six new mononuclear ruthenium complexes Ru2-Ru7 contained -N,N or -N,O ligands were synthesized and characterized by elemental analysis, IR,1H NMR and electrospray ionization mass spectrometry. UV-vis spectroscopy, fluorescence spectroscopy and electrochemistry were also studied. All the six complexes exhibited one oxidation in the range of 0.6～1.0 V, this peak of the complexes was all assigned to the redox of the RuⅡ moieties. The cytotoxicity in vitro was evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Experiments indicated that the Ru2-Ru7 showed significant dose-dependent cytotoxicity to Hela, SGC-7901 and BGC823 tumour cell lines. If auxiliary ligand was the same, the terminal ligand containing -O,O than the ligand-O,N shown obvious cytotoxicity. Ru2 had the selectivity to SGC-7901; Ru3, Ru4 and Ru7 had selectivity to Hela. Ru5 had no cytotoxicity to three test cell lines.4. In chapter 4, a series of 1,10-phenanthroline-based dinucleating bridging ligands and their dinuclear Ru(II) complexes Ru8-Ru10 were synthesized and characterized, their characterization, photophysical and electrochemical properties have been studied. The cytotoxicity in vitro was evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) assay. The study indicated that the Ru8-Ru10 showed significant dose-dependent cytotoxicity to Hela, SGC-7901 and BGC823 tumour cell lines. With the increase of the methylene of bridging ligands, the cytotoxicity of the complexes increased. It is possibly that as the growth of the bridging ligands, complexes were more and more lipophilic, so it’s easy to accumulate in the mitochondria. Cell cycle analysis by flow cytometry indicated that the Ru10 caused cell cycle arrest and accumulated cells in G0/G1 phase. The interaction between complexes and the CT-DNA may be a groove binding mode.5. In chapter 5, a dinuclear ruthenium complex Rull which contained the rigid ligand was synthesized and characterized by elemental analysis, IR, 1H NMR and electrospray ionization mass spectrometry. From the cellular level to study the biological significance of complex. The cytotoxicity in vitro was evaluated by MTT assay, the results showed that Rull was selective to MCF-7. Cell cycle analysis by flow cytometry indicated that the Rull caused cell cycle arrest and accumulated cells in G0/G1 phase. Fluorescence spectrum showed that Rull interact with DNA by inserting way.