Rhodamine-modified Fluorescent Iridium And Ruthenium Anticancer Complex: Synthesis, Characterization And Mechanism Of Action

In the world,cancer,as a common disease,is increasingly threatening the health of all people in the world,especially China with a large population.Chinese cancer statistics released by the National Cancer Center in January 2019 to 2015 show that compared with historical data previously was calculated,the burden of cancer in China and the world continues to rise.Therefore,for the treatment of cancer,the development of anti-cancer drugs is a top priority.Among many anticancer drugs,organometallic complexes have been widely studied,and some half-sandwich complexes of rare metals have been extensively studied,because such anticancer drugs have excellent anticancer activity and better stable structures.The advantages have aroused great interest from researchers.Among anticancer agents,platinum-based drugs have been extensively studied.Carboplatin,cisplatin,and oxaliplatin have been successful in clinical treatment as excellent platinum-based anticancer drugs,but these drugs have certain toxic and side effects,so researchers have turned their attention to other transition metals.Among them,the transition metal ruthenium and cyclometalated iridium complexes have been widely studied in cell imaging reagents and intracellular anticancer mechanisms because of their good fluorescent properties and physical stability,as well as good antiproliferative activity.Although the half-sandwich structure of the complex has good anticancer activity,but this kind of complex generally does not have fluorescence characteristics,so we do not know the specific anticancer mechanism of this kind of complex,there are still complexes in cells The target is unknown and there is no difference between normal cells and cancer cells.The design and research of fluorescent half-sandwich iridium and ruthenium complexes are urgently needed.In this thesis,in order to solve the problems of the above half-sandwich structure complexes,eihgteen fluorescent iridium and ruthenium complexes in four systems were designed,of which eihgt N^N complexed semi-sandwich iridium complexes and four half-sandwiches.N^N coordinated ruthenium complex,four N^N coordinated cyclometalated iridium complexes,and two C^N coordinated semi-sandwich iridium complexes,which make the complexes have excellent resistance to semi-sandwich complexes.At the same time of cancer activity,and has excellent fluorescence characteristics of cycloiridium and ruthenium complexes,the distribution of half-sandwich metal complexes in cells,targets and specific anticancer mechanisms can be studied in detail.In the design experiment of this paper,we first solved the problem that the semi-sandwich iridium complex does not have fluorescence.In the ligand construction process,a fluorophore such as a rhodamine derivative was added to the ligand construction,and By modifying Cp~x on the half-sandwich ring,eight N^N coordination half-sandwich iridium complexes were designed and synthesized,corresponding to the second chapter in this thesis.Secondly,in order to improve the anticancer activity,we adopted by changing the coordination metal,four half-sandwich N^N coordination ruthenium complexes were designed and synthesized.Furthermore,in order to highlight the superiority of the anticancer activity of the half-sandwich structure complexes,we designed the complexes with a ring-iridium structure.Four N^N coordination cyclometalated iridium complexes were synthesized.Finally,in order to compare the effect of C^N and N^N coordination mode on the anti-cancer activity of the complex,we designed and synthesized the coordination mode by changing the coordination mode.Two new C^N-coordinated half-sandwich iridium neutral complexes;the above three groups of changes correspond to the third,fourth,and fifth chapters in this paper,respectively.In this paper,all synthetically designed complexes were characterized by means of nuclear magnetic resonance,carbon,X-ray single crystal diffraction,mass spectrometry,and elemental analysis.Secondly,the stability and fluorescence characteristics of the complex were studied using ultraviolet-visible spectrum and fluorescence spectrum,the effect of the fluorescence and pH changes of the complex and the coenzyme were studied using the above two spectra.Catalytic ability of oxidative dehydrogenation of NADH;Furthermore,the complexes were preliminarily tested on three cancer cell lines(lung cancer cell A549,liver cancer cell HepG2,and human cervical cancer cell HeLa)and two normal cells BEAS-2B and 16HBE by MTT method.Cytotoxicity;Next,ICP-MS was used to test the synergy between the coordination metals and ligands in the complex;Cell flow cytometry was used to test the complex's effect on mitochondrial membrane potential,reactive oxygen levels,related protein content,and cell cycle,The effect of apoptosis;finally,through laser confocal technology,the complex entry method to the cells,the role of the target and the anti-migration mechanism were studied in detail,and proved that the iridium and ruthenium complexes with fluorescent properties Expected to be a candidate for new anticancer drugs for clinical use.