Synthesis, Characterization And Invitro Cytotoxicity Study Of Ruthenium(?) Arene Complexes Of Coumarin ?-Diketonate Derivatives

The discovery of cisplatin has stimulated people's interest in the research of metal anti-tumor drugs.Due to their low cytotoxicity,high efficiency,easy absorption,fast metabolism,and no cross-resistance,ruthenium?II?-arene complexes are widespreadly used in the study of metal anti-tumor drugs.The main factors that affect the biological activity of ruthenium?II?-arene complexes are the structure of the aromatic ring,the chelating ligand and the leaving group.Therefore,the anti-tumor activity of drugs can be changed by adjusting these three factors.As an important natural product,coumarin has important biological activities such as anti-inflammatory,antibacterial,antioxidant,and anti-tumor properties.?-Diketonate is a good kind of chelating ligand.It can coordinate with ruthenium through O and O to form a complex with six membered chelating ring,which can increase the stability of the complex by inhibiting its hydrolysis.Based on this,a series of coumarin?-diketonate ruthenium?II?-arene complexes were designed and synthesized,and their structures were characterized.Then the Log P and stability of selected complexes were studied by UV-vis.A series of experiments were taken to evaluate the bioactivity of the complexes,such as MTT,Annexin V-PI staining,cell cycle analysis,DCFH-DA assay,JC-1 mitochondrial membrane potential assay,wound scratch assay and spectroscopic methods.The main works are shown as follows:1.A series of organoruthenium?II?chlorido complexes with coumarin?-diketonate[??⁶-p-cymene?Ru?coumarin?-diketonate?Cl]?the first kind of ruthenium?II?arene complexes?and replaced by perfluorooctylethyl imidazole[??⁶-p-cymene?Ru?coumarin?-diketonate??perfluorooctyl ethyl imidazole?]PF₆?the second kind of ruthenium?II?arene complexes?were synthesized.These complexes have been characterized by ¹H NMR,¹³C NMR,and elemental analysis.2.The stability of the drugs and its LogP are the prerequisites for ensuring the quality of the drugs and for its efficacy.Therefore,the stability and the Log P of 5h,6h and7h were studied by UV-vis.The results show that the ruthenium?II?-arene complexes with imidazole ligand is more stable than the chloride ligand and the better lipophilicity of the complex was contributed to the introduction of the fluoroalkyl chain.3.The cytotoxic of the complexes were tested towards Hela,MCF-7,MDA-MB-231,A549,MGC-803 by MTT.The first kind of ruthenium?II?arene complexs showed low cytotoxicity,while the second kind of ruthenium?II?arene complexes showed excellent cytotoxicity.It also showed that the cytotoxicity of the complexes of perfluorooctylethyl imidazole ligand were significantly better than that of the non-fluoroalkyl imidazolium complexes.Further investigations on the mechanism revealed that both 6h and 7h could provoke the generation of reactive oxygen species,induce the loss of??m,cause arrest in the G2/M phase,and ultimately cause apoptosis.The cell scratch test showed that 6h can significantly inhibit the migration of MDA-MB-231 cell.3.DNA and protein are usually the target of drug.therefore,studying the interaction of drug with DNA or protein is of great significance for the development of drug.The reactivity toward the ct-DNA and BSA of 5h,6h and 7h were studied by UV-vis spectroscopy,fluorescent spectrum.The preliminary results showed that the complexes could interact with ct-DNA through intercalation mode and quench the fluorescence of BSA by a static quenching mechanism.6h had the strongest binding ability to DNA and 5h had the strongest interaction with BSA.