Synthesis And In Vitro Anticancer Activity Of Aryl Ruthenium (?) Complex Containing N^N Bidentate Ligand

In today's society,due to the high incidence of cancer and high mortality,people had attracted widespread attention.Although the platinum-based anti-cancer drugs used in clinical treatment had remarkable therapeutic effects,however,their toxic side effects were unavoidable.Therefore,the development of high-efficiency,low toxicity,and targeted anti-cancer drugs was one of the current research hotspots.Seven aryl ruthenium complexes containing N^{^}N ligands were synthesized in this thesis.The purity and structure of these complexes were determined by chemical characterization.The anti-cancer activity of the MTT assay was screened in vitro,and the more active complexes were selected for later cell detection.The targeting of the complexes was analyzed by cell imaging techniques.The hydrolysis,catalytic properties,and the reaction with BSA of the complexes were analyzed by using nuclear magnetic and UV spectrophotometers.In the following sections,we will introduce the research content in detail.The thesis was divided into four chapters.The first chapter was the introduction of the thesis.The research background of anticancer drugs was mainly introduced,and the significance of the topic and the content of the research were briefly described.In the second chapter,we designed and synthesized four different imino N^{^}N bidentate ligands,then used as main ligands to bind with metal ruthenium???to synthesize four aryl ruthenium???complexes[??⁶-bz?Ru?N^{^}N?Cl]PF₆.Through chemical characterization,the purity and structure of the complexes were determined.Through in vitro cytotoxic activity experiments,it was found that complex 4[??⁶-bz?Ru?L₄?Cl]PF₆ had high anticancer activity and no toxicity to normal cells,showing good cell selectivity.Afterwards,lung cancer cells A549 was selected for subsequent cell experiments.Through a large number of in vitro cell experiments,we found that the complex 4 could arrest the cycle of cancer cell A549 in G₂/M phase;secondly,it could induce the obvious apoptosis of cancer cells;then it could lead to higher ROS levels in cancer cells and could damage the mitochondrial membrane potential of cancer cells.Further experiments also showed that the complex 4 was an effective catalyst for converting the coenzyme NADH into NAD⁺,and it can also react with BSA to quench its fluorescence.In the third chapter,three N^{^}N didentate ligands containing methoxy,chlorine and fluorine were used as main ligands and combined with[??⁶-p-cymene?RuCl₂]₂ to synthesize corresponding complexes[??⁶-p-cymene?Ru?N^{^}N?Cl]PF₆.Through the interaction with cancer cells HeLa cells and A549 cells respectively,the three complexes showed good cytotoxicity,in which the complex 6[??⁶-p-cymene?Ru?L₆?Cl]PF₆ had the best anticancer activity.A series of follow-up experiments were then designed for complex 6 to further explore its anticancer mechanism.The experiments results showed that complex 6 could target lysosomes.By flow cytometry,complex 6 could arrest the cell cycle of cancer cell A549 in G₁ phase;secondly,it promoted higher ROS levels in cancer cells;and could destroy the mitochondrial membrane potential of cancer cells.The fourth chapter was the conclusion of the thesis.The thesis mainly summarized the results and provided a new direction and goal for the future research of anticancer drugs.