Design,synthesis,and Mechanism Of Small Molecules Targeting Biological Thiols As Potential Drugs And Probes

Reactive oxygen species(ROS),which play a key role in many biological processes,can function as signaling molecules regulating numerous cellular processes and sustaining cellular homeostasis at low concentrations.However,ROS may induce cell oxidative damage and eventually cause apoptosis at high concentration.Therefore,it is significant to find some small molecular compounds which can regulate intracellular oxidation reduction state.Biological thiols,including small molecule thiols,such as cysteine(Cys),Homocysteine(Hcy),glutathione(GSH),and protein thiols,play vital roles in maintaining cellular redox homeostasis.The oxidation of biothiols participates not only in the defense against oxidative damage but also in enzymatic catalytic mechanisms and signal transduction processes.In this thesis,We focus on the interaction between small molecules and biological thiol to interfere with the intracellular redox balance including the following studies:(1)Synthesis of selenium-containing organic compounds which can simulate glutathione peroxidase(GPx)function and protective mechanism of PC12 cells oxidative damage model by these compounds;(2)The selenium-containing compounds can react with biological thiols to generate ROS via redox cycling,then induce apoptosis of tumour cells through oxidative stress;(3)Design and synthesis of a novel probe for the specific detection of thiols,and application to reversibly label the sulfhydryl protein.The contents are summarized in following four chapters:Chapter 1: We br ief ly introduced biological thiols and ROS as well as their function in the organism and the relationships with disease.Then the development of fluorescent probes for detection biological thiols by category was outlined.In the end,we reviewed the function of the trace element selenium for the organism and the development of organic selenium compounds.Chapter 2: We synthesized a series of selenium-containing organic compounds according to the reports,then the GPx activity of these selenium-containing organic compounds was evaluted,and we obtained a better GPx activity diselenide DTDS.The further studies identified that DTDS can not only reduce the accumulation of ROS in the PC12 cell,but also activate Nrf2 pathway within the cell and induce expression of phase II enzyme genes to protect PC12 cells from oxidative damage.These results make it possible to send DTDS as a potential neuroprotective molecule.Chapter 3: In cells,the selenium-containing compounds can be metabolized to selenols,which react with cellular thiols to generate ROS via redox cycling,leading to oxidative stress to cells.In this chapter,we evaluated the antitumor activity of several organoselenium compounds and found that diselenide 12 have a good inhibition on the growth of Hep G2 cells.In the further study,we noticed that diselenide 12 can not only induce superoxide anion production to accelerate ROS accumulation in tumor cells,but also inhibit cellular antiox idant system to decrease the ability of cells against oxidative stress.Diselenide 12 can activate the apoptosis signaling pathways,and ultimately induce apoptosis of Hep G2 cells.Chapter 4: A turn-on and thiol-specific probe BODIP Y-TS that utilizes the thiosulfonate scaffold as a thiol recognition unit was reported for the first time.BODIP Y-TS displays low toxicity,and has high sensitivity and fast response towards thiols.Furthermore,BODIPY-TS selectively labels protein thiols with enhanced fluorescence signal via forming mixed disulfide bonds with protein sulfhydryl groups,these mixed disulfide bonds could be easily cleaved by physiologically reducing agents to completely restore the proteins ’ function,thus providing the first case for traceless and turn-on label of protein thiols.BODIP Y-TS is also readily applied to determine protein disulfides and S-nitrosylated proteins in cells.