Synthesis And Anticancer Activity Studies Of Novel Ruthenium (Ⅱ) Complexes

Malignancies serious harm to human health, Seeking new chemotherapy drugs withhigh efficacy, low toxicity and can targeting tumor became the focus of domestic andforeign research. Cisplatin, carboplatin and oxaliplatin as the representative of the platinummetals showed significant anti-tumor efficacy in the clinical treatment. The application ofplatinum anticancer drugs are limited for toxicity, such as Nausea and vomiting, bonemarrow suppression and neurotoxicity. Therefore, to find new chemotherapy drugs withhigher efficacy and lower toxicity that can target tumor became a new research goal forscientist. Ruthenium complexes can achieve this goal because them anti-tumor activity issimilar to the platinum complexes.12kinds of ruthenium metal complexes had beendesigned, synthesized and characterized in this research.The IC50was evaluated byBel-7402, A549, SKBR-3and MG-63four cell lines. To evaluate the complexes can induceapoptosis a series of experiments was taken, such as cellular uptake assay, AO/EB staining,cell cycle analysis, ROS analysis assay and mitochondrial membrane potential analysisassay. Western blotting analysis was taken to investigate the mechanism of apoptosis thatinduced by the complexes. Following are the describes of the specific research.In the chapter2, the ligand THPIP was synthesized with phenanthroline-5,6-dione and2-hydroxy-3,5-di-tert-butyl-benzaldehyde, four ruthenium complexes RuA1-A4weresynthesized with THPIP, bpy, dmb, phen and dmp. IC50values of the four cell lines areabout25μM, more lower toward A549cells. Other assays, such as cellular uptake assay,AO/EB staining and mitochondrial membrane potential analysis assay, proof the complexes can be uptaken by A549and induce cell apoptosis.In the chapter3, the ligand HMNP was synthesized with phenanthroline-5,6-dione and3-nitropropionic-4-hydroxy-5-methoxy-benzaldehyde, then four ruthenium complexesRuB1-B4was synthesized. IC50values of the four cell lines are about50μM, more lowertoward A549cells. Other assays proof the complexes can be uptaken by A549and inducecell apoptosis.In the chapter4, The nitro group in the complexes RuB1-B4were reduced to an aminogroup became complexes RuC1-C4. IC50values of the four cell lines are about30μM thatindicate the antitumor activity significantly enhanced compared to RuB1-B4. complexesRuC1-C4can also induce apoptosis through AO/EB staining and mitochondrial membranepotential analysis assay.In the chapter5, to clarify the mechanism of apoptosis of A549cells that induced bythe complex RuA1, western blotting assay was taken. The result showed that the proteinsabout Bad, Bax, Caspase-9and Caspase-3were activated, the Bcl-2were Bcl-2downregulation. That further indication the mechanism of apoptosis of A549cells thatinduced by the complex RuA1by way of mitochondrial pathway.