Targeting On The Mitochondria Of Ruthenium(â…¡) Complexes: Synthesis And Anticancer Activity Studies

This paper designed and synthesized a series of ruthenium(II) polypyridyl complexes and screened their antitumor activity by MTT experiment. The signal transduction pathway of these ruthenium polypyridyl complexes was detected in a variety of ways, such as cellular uptake, flow cytometry, single cell gel electrophoresis, detection of reactive oxygen species, mitochondrial membrane potential, AO/EB double staining, Hoechst 33342 staining and western blotting analysis. For some tumor cells, some of these polypyridyl complexes display higher cytotoxic effect than cisplatin under identical condition, such as 2D, 3C on A549 cells and 2A on Bel-7402.The thesis consists of six chapters.In the chapter 1, it summarized the research progress of antitumor activity of the transitional metal complexes, illuminated the significance of this paper and the huge potential of the ruthenium complexes as antitumor drugs. In addition, it outlined the main signal transduction pathway of apoptosis and introduced the methods of antitumor studies in detail.In the chapters 2 and 3, two asymmetric ligands and their eight ruthenium(II) polypyridyl complexes were synthesized. We found that all of them have good antitumor activity in vitro, moreover, ruthenium(II) polypyridyl complexes display enormous prospect in photodynamic therapy. It was verified that these ruthenium(II) polypyridyl complexes can enter A549 cells and accumulate in the nucleus and cytoplasm. In addition, they can induce apoptosis of A549 cells and increase of reactive oxygen species levels in the cell, induce G0/G1 phase arrest in A549 cells. The levels of apoptosis proteins like Caspase-3,-7 were increased and the levels of anti-apoptotic proteins including Bcl-x and Bcl-2 were decreased.In the chapter 4, a ligand of dppz derivate and four novel corresponding ruthenium(II) polypyridyl complexes were synthesized. The cytotoxicity in vitro was explored in the first and then selected the Bel-7402 as the research object. We explored the preliminary mechanism of anticancer.In the chapter 5, a symmetrical ligand bdppn and four corresponding ruthenium(II) polypyridyl complexes were synthesized. We selected the Bel-7402 as the goal of our research through the cytotoxicity in vitro, and studied the intracellular signal pathways in Bel-7402 after incubation with complexes through a variety of ways.In the chapter 6, the antitumor activity and mechanism of 16 complexes were summarized and clarified the direction of the follow-up study.