Regulation And Mechanism Of Small Molecule Drugs On Cellular Redox System

Reactive oxygen species(ROS),as the products of intracellular redox metabolism,play a “Double-edged sword” role in the process of life.On the one hand,ROS,as a signal molecule,regulates gene expression,Epigenetics and ultimately cell function by regulating the function and activity of proteins and transcription factors.On the other hand,excessive ROS can cause permanent damage to biological macromolecules such as DNA,lipids and proteins,and ultimately have a profound impact on cell death and the development of potential diseases.Targeting the fact that tumor cells are more sensitive than normal cells to drugs that stimulate intracellular ROS production,drugs that induce oxidative stress and then kill tumor cells are currently one of the major tumor therapeutic strategies.The thioredoxin(Trx)system serves as an important intracellular redox regulatory system that is essential for maintaining tumor phenotype and supporting tumor growth and metastasis and is associated with tumor drug resistance.Therefore,Trx system is a potential target for cancer therapy.This thesis focuses on the discovery of potential Thioredoxin reductase(Trx R)selective inhibitors by chemical modification and the exploration of the mechanism of Trx system and its influence on the therapeutic efficacy by combining it with other ROS-regulating therapies.The main content is as follows:In chapter 1,the introduction summarizes the intracellular redox metabolism and its role in the treatment and development of cancer.The Trx/Trx R system and its regulatory mechanism on downstream redox proteins and some classical Trx R inhibitors were summarized.This paper briefly introduces photodynamic therapy and reviews the development of Iridium(Ш)photosensitizers.In chapter 2,a series of Piperine derivatives were designed and synthesized,and their biological activities were evaluated.Through the screening experiment,the analogue P-B5 was selected,whose cytotoxicity was about 4 times higher than that of the parent compound.Further study of its biological activity showed that P-B5 could selectively inhibit Trx R activity,leading to intracellular oxidative stress and ultimately induced apoptosis of tumor cells.The biological activity of P-B5 provide guidance for further modification and application of Piperine analogues as Trx R inhibitors.In chapter 3,a series of potential Trx R inhibitors containing sulfonamide skeleton were designed and synthesized.Their cytotoxicity to different types of tumor cells and their inhibitory effects on Trx R in vitro were evaluated.The selected compounds A3 showed high cytotoxicity to He La cells and specific inhibition to Trx R.Further mechanistic studies have shown that it selectively inhibits Trx R by targeting Sec and induces intracellular oxidative stress that ultimately leads to tumor cell apoptosis.In addition,compound A3 showed obvious activity in the migration and invasion of tumor cells,and also inhibited tumor growth in mice.In chapter 4,the activity of Iridium(Ш)complexes as photosensitizers in photodynamic therapy was evaluated.After the initial cytotoxicity screening,the complex PC9 with the highest phototoxicity index was selected,and the biological activity of PC9 in cells was further investigated.When PC9 was exposed to light,the He La cells produced large amounts of ROS.PC9 can effectively target mitochondria as photosensitizer,destroy the regulation mechanism of redox in cells,and finally lead to apoptosis.Iridium(Ш)complexes as photosensitizers can strongly target organelles and make PDT effects more sensitive by impairing intracellular redox regulatory mechanisms,a line of thought for photosensitizer research first reported in this paper,it provides a new perspective for the design and development of effective new photosensitizers in the future.In chapter 5,a novel Trx-regulated downstream protein,Bmi1,was discovered.The sulfhydryl group of Bmi1 is easy to be oxidized,and the molecular weight of BMI1 protein changes after oxidative treatment,which can be recovered by Trx system.In addition,the synergistic inhibition of cell proliferation with inhibitors of the Trx system and Bmi1 suggests a novel anti-tumor therapeutic strategy.In the sixth chapter,we summarize the work of this thesis and make a prospect for the future development of this subject,mainly focusing on the development of photosensitizers and the redox regulation mechanism of Bmi1.