Rational Design And Action Mechanisms Of Functional Ir(?) Complexes For Cancer Therapy

As a disease of high mortality in the world,malignant tumor has become the major killer of public health.Cisplatin,a representative of platinum metal complexes,plays an important role in clinical chemotherapy.But serious side effects of the platinum metal complexes limit their clinical application,inspiring urgent need for seeking new anti-cancer drugs.The transition metal complexes of iridium(?),with d~6 electronic structure,for long luminescence lifetimes,high photostability,easy modification and cellular uptake,have been employed as biological probes.Meanwhile,some iridium(?)complexes show great anticancer activity.This thesis is based on rational designing and synthesizing series of iridium(?)complexes,a brief introduction of each chapter of the thesis is listed below:1.We introduced the selenium diazole into the metal iridium(?)complex Ir-CHO through the formation of imine bond.It was found that the selenium-containing metal complex Ir-Se has improved hydrophobicity and anti-tumor activity compared to Ir-CHO.Interestingly,the solid of Ir-Se and its solution do not show any luminescent light,but,its solution can be lighted-up in a weakly acidic environment with p H = 6.8.To further explore the phosphorescence quenching of selenium-containing iridium(?)metal complex,oxadiazole and thiadiazole were synthesized to modify the accessory ligand and corresponding iridium(?)complexes.Antitumor activity was significantly improved with the inducting benzole diazole and phosphorescence quenching was caused by selenium atoms.In addition,the luminescence intensity of the complexes was enhanced and bathochromic-shift was observed.Further investigation revealed that benzothiodiazole-containing complex Ir3 activates apoptosis pathway and induces cell cycle arrest by reducing ROS levels in cells,which inhibited the proliferation of MDA-MB231.2.Taking advantaging of the characteristics of tumor microenvironment,metal complexes with various biological response properties are one of the hot spots in the current research of metal complexes.Boron element has good biocompatibility,binding ability with N or O atoms.So we designed and synthesized the acid-responsive Iridium boron complex Ir-DPB,which was based on the known information that boronic acid with aminoethanol can form acidic sensitive B-O and B-N bond.The data shows that Ir-DPB has greatly improved the lipophilic and luminescence properties with the comparison of the precursor complexes,while at the same time the selective selectivity of tumor cells and normal cells under acidic condition was also inproved.Mechanism studies have shown that the induction of apoptosis and the arrest of G0/G1 phase are the ways in which Ir-DPB exerts antitumor activity.3.The targeted therapy can greatly enhance the therapeutic effect and reduce the toxic and side effects.In the work,targeting molecular biotin was connected to auxiliary ligand and strong electron-withdrawing groups of nitrobenzene was connected to auxiliary ligand.In the end,we synthesize the targeted metal iridium(?)complex Ir-NB which can be phosphorescence quenching in neutral environment and lighted-up in an acidic environment.In addition,iridium is the heavy metal atom,so the feasibility of Ir-NB using as radiotherapy sensitizing agent was studied.The data display the amount of single drug and X-ray is greatly reduced when Ir-NB was used in radiotherapy,and it can be used as a safe radiotherapy sensitizer.In summary,three series of metal iridium complexes were synthesized respectively.By analyzing the structure-activity relationships among the compounds,the differences in their luminescent properties and biological activities were investigated and discussed.Their antitumor mechanism was detailed explored.