The Preparation Of Semi-sandwich Structure Metal Ruthenium And Iridium Complexes And Their Anticancer Activity In Vitro

Cancer is one of the killers threatening human health,and deaths caused by cancer account for one-sixth of global mortality.Surgery,chemotherapy and radiotherapy are traditional methods of clinical treatment of cancer,and chemotherapy still occupies an important position in cancer treatment.The successful debut of platinum drugs in the field of anti-cancer has attracted more and more metal-based anti-cancer drugs.In this paper,a series of semi-sandwich metal ruthenium and iridium complexes were synthesized using pyridine skeletons modified with ferrocene and triphenylamine as ligands.The composition and structure of the target complex were characterized by X-ray single crystal diffraction,nuclear magnetic resonance,elemental analysis and mass spectrometry.Ultraviolet-visible spectroscopy and fluorescence spectroscopy were used to examine the stability,biocatalysis and protein binding of the complex.MTT colorimetric method was used to explore the anti-cancer activity of the compound,and the compounds with better activity were screened.The mechanism of action was studied in depth using flow cytometry and two-photon laser microscope.1.Ferrocene is an active research field in cancer therapy,and in vivo experiments have shown good tumor cell growth inhibition rate,showing its good application prospects in the field of anti-cancer.However,compared to other organometallic anti-cancer drugs,ferrocene derivatives still exhibit the disadvantages of low activity,poor targeting,and large side effects.In this paper,a series of ferrocene phenylpyridine?C^N?bidentate ligands were designed and synthesized using ferrocene as the basic unit,and then coordinated with iridium to prepare a series of iron-iridium heteronuclear metal anticancer complexes.Under the same conditions,the MTT experimental results show that the complex has a broad-spectrum anticancer activity against A549?lung cancer cells?,Hela?cervical cancer cells?,HepG2?hepatoma cancer cells?,and the anticancer activity can reach 7 times that of cisplatin.The iron-iridium complex shows better anticancer activity than the single ferrocene and metal iridium complex,confirming our conjecture that the two have a synergistic effect.In addition,the configuration of the ligand also has an effect on the anti-cancer activity of the complex.Compared with the cis-configuration,the trans-configuration complex has better activity,and the effect of the structure-activity relationship on the anti-tumor activity is analyzed through quantitative calculation simulation.UV-vis spectroscopy and NMR results confirmed that the complex can maintain structural stability under physiological conditions.UV-vis spectroscopy,flow cytometry and cyclic voltammetry proved that the complex has a good catalytic effect on the conversion of nicotinamide adenine dinucleotide?NADH?and can induce intracellular reactive oxygen species?ROS,¹O₂?Accumulation and exhibit good redox properties,revealing the mechanism of oxidative anticancer action of the complex.In addition,two-photon laser confocal detection showed that these complexes accumulate in the lysosome after entering the cell through an energy-independent cell uptake mechanism,destroying the integrity of the lysosome and leading to the outflow of hydrolase,resulting in the mitochondria of peripheral organelle dysfunction?decreased membrane potential?,eventually leading to apoptosis.At the same time,the complex can effectively inhibit cell migration and colony formation.2.As a representative of non-platinum antitumor drugs,metal ruthenium complexes have been evaluated by researchers as the most promising metal anticancer drugs due to their advantages of low toxicity and easy absorption,and some complexes have been successful.Enter the clinical trial stage.In order to better clarify the anticancer mechanism of metal ruthenium,we introduced triphenylamine compounds with good fluorescence properties into the metal ruthenium skeleton,and designed and synthesized a series of triphenylamine modified semi-sandwich-structured metal ruthenium complexes,the introduction of triphenylamine,effectively improves the lipid of the metal ruthenium complex solubility.MTT test shows that the complex has good anti-cancer activity in vitro against A549?lung cancer cells?,Hela?cervical cancer cells?and HepG2?hepatoma cancer cells?,far superior to the widely used cisplatin on the market(IC₅₀:2.4?9.2?M),Ru2 and Ru4 have more prominent anti-cancer activity against the three cancer cells.UV-vis spectroscopy detected the binding effect of the complex and bovine serum albumin?BSA?,and combined with thermogravimetric experiments to confirm the biological stability of the compound in different environments.Two-photon laser microscopy detected that the way the compound enters the cell is non-energy inhibition,which can target the lysosome and cause lysosomal damage.The results of flow cytometry showed that the complex could induce a decrease in mitochondrial membrane potential,block the cell cycle,and ultimately induce apoptosis.At the same time,the complex can effectively inhibit cell migration,confirming the dual anti-cancer mechanism that the target complex inhibits tumor cell migration and induces lysosomal damage.