The Construction Of Star Polymer-based Bioorthogonal Organometallic Catalytic Systems

Bioorthogonal catalysis refers to the catalysis of non-natural chemical reactions in complex biological environments.This cutting-edge field intersects catalysis science with chemical biology,life medicine,biochemistry,nanotechnology,and other disciplines.By utilizing bioorthogonal catalytic reactions,molecular-level modifications of biological systems can be carried out,allowing for the regulation,optimization,or modification of biological functions.This holds great potential for future biological applications.Currently,the development of bioorthogonal catalysis systems primarily relies on the screening and optimization of organometallic complexes,but this is limited by factors such as solubility,stability,and biocompatibility in complex biological environments.To address these issues,strategies that utilize scaffold structures with higher structural hierarchies to load organic metal catalysts have shown promising prospects.Various bioorthogonal catalysis systems based on scaffold structures such as bio-macromolecules and artificially synthesized polymers have already been successfully applied to catalysis within living cells.However,in polymer-based bioorthogonal catalysis systems,the lack of well-defined scaffold structure and structure-performance relationship still constrain its further development.Therefore,designing and constructing precise and adjustable scaffold structures,understanding the relationship of scaffold structure with catalytic performance,and rationally optimizing catalysis systems are important scientific problems that require attention.This thesis focuses on two aspects:on one hand,a polymer scaffold platform with well-defined and modularly adjustable structures is constructed,and methods for studying the scaffold-catalyst structure-performance relationship are developed;on the other hand,new concepts and systems of bioorthogonal catalysis have been explored,including new organometallic catalysts,bioorthogonal substrates,and methods of supramolecular engineering of the catalytic systems.The main research content and progress of this thesis are as follows:（1）We have developed a modular synthetic platform to prepare di-block brush-arm star copolymers（DBSPs）using a convergent"graft-to"approach by combining the ring-opening metathesis polymerization（ROMP）with a post-polymerization modification strategy.Firstly,we designed and synthesized a POSS derivatives with octa-functionalized enyne terminator（POSS-EY₈）.The terminator can undergo enyne metathesis reaction with the ruthenium active center,thus coupling with the polymer chain at the ending ruthenium.Based on this reaction,we first synthesized the block copolymer structures via ROMP and then added POSS-EY₈molecules to couple the polymer chains to the POSS core at the eight sites through enyne metathesis mediated conjugation,to afford a star-shaped polymer.The combination of ROMP and post-polymerization modification allowed us to conveniently synthesize a series of well-defined and modularly controllable star-shaped polymer structures.We characterized the structure of these DBSPs in detail using multiple characterization methods,including study the local microenvironment of different positions of the polymer by introducing environment-sensitive fluorescence and paramagnetic probes,laying the foundation for further understanding the relationship between scaffold structure and catalytic performance.These DBSPs have good water solubility and a monodisperse size distribution in dilute aqueous solutions,with a hydration radius of about 10 nm.In addition,DBSPs have hydrophobic internal cavities that provide a site for catalyst loading and catalytic reaction.（2）Through covalent modification or physical encapsulation,we can embed the organic metal catalytic active center into the interior of star-shaped polymer scaffolds,constructing polymer-based bioorthogonal catalytic systems based on tris-triazole ligand-copper,iron porphyrin,and other organic metal catalytic active centers.Using a fluorescence-generating model reaction,we studied the catalytic behavior of such catalytic systems in aqueous solution.The results show that these catalytic systems can effectively catalyze reactions in aqueous solution.The hydrophobic cavity within polymer scaffolds enhances the substrate enrichment effect,leading to higher catalytic efficiency compared to small molecule catalysts.Furthermore,we applied polymer-based catalytic systems in complex cellular environments.Among them,the polymer-based catalyst based on the tris-triazole ligand-copper can effectively catalyze the carbamate cleavage reaction in the extracellular environment,but the catalyst has no obvious catalytic effect in the intracellular environment.It is speculated that the copper catalytic center is poisoned by the high concentration of glutathione molecules in the cell,leading to loss of catalytic activity.Therefore,we endeavored to employ catalysts based on glutathione-compatible iron porphyrin polymers in intracellular environments.Our findings indicate that these catalysts can efficiently catalyze the reduction reaction of azide within intracellular environments.（3）To further optimize the bioorthogonal catalytic systems,we are focusing on expanding the range of organometallics catalysts and exploring supramolecular engineering approaches to enrich the substrates and anchor the catalysts on the cell surface.First,we synthesized various NHCs-metal complexes containing norbornene groups as ROMP monomers.Based on the DBSPs polymer synthesis method,a series of DBSP catalytic systems were constructed.We screened and optimized the catalytic performance of the substrates under different medium conditions.Among them,DBSP-Pd demonstrated remarkable ability in catalyzing the hydrolysis of C-m Rho.Moreover,by incorporating supramolecular recognition units into the catalytic system,we were able to endow it with novel functionalities.For instance,we utilized a highly efficient host-guest recognition system based on cucurbituril-adamantane to immobilize the catalyst on the surface of living cells,which could potentially pave the way for investigating the delivery of catalytic systems by cells.