Construction And Application Of Novel Alkenyl Thioether Dynamic Covalent Bond System

Dynamic covalent bonds,which can be as stable as covalent bonds,and dissociate as noncovalent bonds,are ideal tools for exploring the nature mechanism of cellulars,drug delivery and supramolecular construction for its unique characteristics.Extremely important role.However,more and more dilemmas have emerged with the gradual developing of basic scientific,such as the exploration of life mechanisms,the development of new drugs,and the construction of prodrug controlled release systems.However,in recent years,few new dynamic covalent bond systems have been proposed and studied systematically.It is in this context,for the first time we demonstrated the alkenyl thioether dynamic covalent bond and the characteristics were systemically investigated.The research objective of this paper and the follow-up work of our research group is to systematically explore the basic physical and chemical properties of this new dynamic covalent bond system,and provide insights into complex life mechanisms,drug delivery,and peptide probes and peptide drug development.The application prospects of the aspect provide experience and guidance for solving the bottleneck problem of the traditional dynamic covalent bond system in these fields.This work including the following five chapters:Chapterl,Summarizes the development of dynamic covalent bonds and the properties of several dynamic covalent bonds and their applications in the exploration of life mechanism,molecular assembly and drug delivery.The concept of alkenyl thioether dynamic covalent bond was put forward,and its basic chemical properties and application prospects were summarized.On this basis,the research ideas,content and significance of this work were proposed.Chapter 2,A dynamic covalent system model was constructed.The stability and kinetics of the alkenyl thioether dynamic covalent bond with active thiol groups were studied.Explore the application prospects of this new type of dynamic covalent bond in the exploration of life mechanism,molecular assembly and drug delivery.Chapter 3:The delivery system based on thiol-disulfide exchange reaction on cellular membrane surface has received increased attention,but the mediating mechanism is almost ignorant because of the bidirectional reactivity of disulfide bonds toward reactive thiols.In this work,we developed thioether-bonded fluorescent probes that enable us to explore thiol-mediated thioether(and disulfide)exchange reactions on the cell surface through fluorescence recovery and/or cell imaging.We demonstrated that our thioether bonded probes can be efficiently cleaved through thiol-thioether exchanges with exofacial protein thiols and/or glutathione(GSH)efflux and the exchanges mainly take place on the cell surface.Chapter 4:Herein,we designed and synthesized an novel environment-sensitive fluorescent probe based on a hemicyanine derivative which containing two asymmetric thiol-reactivity moieties and fused a ester group to control the transmembrane transportation of the probe.For the first time,we realized the visualization of both monothiol proteins and dithiol proteins synchronously in living cells.Chapter 5:Poly(alkenyl thioether)s delivery system was developed based on the P-OEGMA brush polymer.The hydrophobic dye,Bodipy,was modified to the S-terminus of the Poly(alkenyl thioether)s delivery system through a alkenyl thioether bond linker.The cleavage of-C-S bond by the reduction of GSH and confocal imaging analysis indicates that the secedeing of hydrophobic components at S-terminal with nearly 100%efficiency.This delivery system is particularly suitable for non-internal drug/probe delivery system.