Design, Synthesis And Biological Properties Of Ruthenium/iridium Metal Anticancer Complexes

At present,platinum-based drugs used clinically have good pharmacological properties and have good therapeutic effects on various solid tumors.However,the nephrotoxicity and drug resistance of this type of platinum metal drugs greatly limit its efficacy.Therefore,scientists have gradually turned their targets to other metals,such as ruthenium,iridium,osmium and rhodium complexes.Compared with platinum drugs,these anti-cancer complexes have low toxicity,no drug resistance and rich optical properties.The introduction of some natural ligands can change the lipophilicity of these complexes,improve the anti-tumor activity and solubility of the complexes,and achieve the effect of synergistic treatment.We designed and synthesized a new type of Indole Ruthenium complex 1 with anti-tumor activity.The ligands and complexes were characterized by ¹H NMR、ESI-MS and elemental analysis.Using a fluorescence spectrophotometer and an ultraviolet-visible spectrophotometer,it is found that the complex can emit fluorescence under the excitation of a certain wavelength of light,which realizes the visual imaging of the complex in the cell.The introduction of the ligand greatly improves the liposolubility of the complex,which makes it easier for the complex to enter the cell and makes Complex 1 show good anti-tumor activity compared with the ligand Indole and the precursor Ru（bpy）₂Cl₂.In order to further understand the mechanism of Complex 1 induced tumor cell death,we used flow cytometry,confocal imaging and western blotting to explore.The results show that the complex Ru-Indole can be enriched in the mitochondria and lysosomes of tumor cells.The complex 1does not induce cell death through apoptosis and cycle arrest,but induces cell death by changing the mitochondrial membrane potential and inducing autophagy.In the third chapter,the indole derivative is chemically modified by aldol condensation reaction to obtain ligand L,and the obtained ligand is coordinated with aryl metal iridium and aryl metal ruthenium complexes to obtain complex 2-3.In vitro proliferation inhibition experiments found that the two aryl metal complexes have good cytotoxicity,complex 2 has the best anti-proliferation effect on He La cells.Studies have found that complex 2 is enriched in the cytoplasm and mitochondria,and is mainly distributed in the cytoplasm.It can induce He La cells to produce ROS and at the same time induce a decrease in mitochondrial membrane potential,but does not block the cell cycle.Further research found that complex 2 does not induce cell apoptosis and necrosis,but induces cell death through autophagy.In Chapter 4,we chemically modify three natural ligands to obtain ligands L2-L4,and chemically modify ruthenium trichloride to obtain metal prodrug complex4,and combine complex 4 with ligands L2-L4 The click reaction is carried out under copper catalysis to obtain complexes 5-7.The three complexes were characterized by NMR,ESI-MS and other methods.Cytotoxicity experiments show that complex 5 has no cytotoxicity(IC₅₀>200μM),complex 6 has certain cytotoxicity(IC₅₀ is between21.50-37.12μM),and complex 7 has good cytotoxicity,which is very cytotoxic to A2780 cells.The best cytotoxicity(IC₅₀=1.61μM).Studies have shown that the three complexes have good fat solubility and stability.Through intracellular experiments,it is found that complex 7 is mainly located in the lysosome of A2780cells,which can induce the production of reactive oxygen species（ROS）,and induce cancer cell death by means of cell necrosis.At the same time,complex 7 can block the cell cycle in The S phase further leads to cell death.In short,this paper selects the metal Ru,Ir as the center,a total of seven complexes 1-7 were designed and synthesized.By using different ligands to modify the two metals,the anti-tumor activity is improved,and the way in which the complexes induce cancer cell death has been deeply explored.