Dendritic Polymers Act As Glutathione Peroxidase Mimics

Based on the precisely controlled molecular structure,unique physical andchemical behavior and great potential in the application of catalytic field,dendritic polymer has aroused great interest from the scientists worldwiderecently. Compared with traditional linear polymeric catalysts, dendriticpolymer-based catalysts with nanometer size offer a unique opportunity tocombine the advantages of homogeneous and heterogeneous catalysis, whichmakes it possible to design highly efficient catalysts at molecular level. Enzymesare highly efficient catalysts which could selectively catalyze specific reactions.To design catalysts with high efficiency and selectivity like enzymes and tounderstand the mechanism of the catalysis are one of the goals scientists arepursuing now. Glutathione peroxidase (GPx) is a mammalian antioxidantselenoenzyme which protects biomembranes and other cellular components fromoxidative damage by catalyzing the reduction of a variety of hydroperoxides(ROOH), using glutathione (GSH) as the reducing substrate. GPx mimics hasbeen involved in the treatment of a variety of diseases, including aging,Alzheimer's disease, inflammation, and some certain cancers. Owing to theinstability and short half-time of natural GPx, scientists have put more efforts onthe study of GPx mimics. To design and synthesize highly efficient GPx mimics isnow a challenge to both chemists and biological scientists. Aim of this thesis is todesign and synthesize highly efficient dendritic polymer-based GPx mimics and tostudy the factor that governs the activity of the GPx mimics, thus open a newavenue for highly efficient GPx mimics.In chapter Ⅰ, the basic concepts of dendritic polymer and GPx were brieflyintroduced. Recent developments of using dendritic polymer as catalysts andbiomimics and progress of GPx mimics were also shortly summarized.In chapter Ⅱ,we reported the synthesis of the three generations of Fréchet-typepoly(aryl ether) dendrimers with diselenide core, which demonstrategeneration-dependent glutathione peroxidase (GPx) activity with initial reductionrate as high as 2431.20 μM?min-1 for the third generation product. To the best ofour knowledge, this rate is among the highest of the organic systems mimickingGPx. In contrast to Ebselen catalysis determined under the same condition, forexample, the remarkable rate enhancement of 1400-fold is observed for dendrimerG3. We speculated that the high GPx activity of G3 originates from thehydrophobic microenvironment provided by its macromolecular structure. Withthe increase of the generation, the interaction between dendrimer catalyst andsubstrate will increase, leading to the great enhancement of the GPx activity forhigher generation dendrimers. We have measured the binding constants betweenthe dendritic GPx mimics and the substrate PhSH and found that the bindingconstant between PhSH and G3 are well above G1 and G2. By adjusting the ratioof the solvent, we could also change the conformation of the dendritic GPxmimics, thus alter the microenvironment, leading to fine tuning the activity ofGPx mimics.In chapter Ⅲ We have described the synthesis of a series of poly(aryl ether)dendrimers with telluride in the core and oligo(ethylene oxide) chains at theperiphery, a linear polymer with telluride at the backbone and oligo(ethyleneoxide) at the side chains which act as glutathione peroxidase (GPx) mimics. Theseseries of compounds were well characterized by 1H-NMR, 13C-NMR and ESI-MSand GPC. Using different ROOH (H2O2, cumene hydroperoxide) for testing theantioxidizing properties of these compounds, we have found that from generation0 to 2, the activity of the dendritic GPx mimics first decreased and then increased.This can be explained on the basis of a greater steric hindrance, going fromgeneration 0 to 1, and stronger binding interactions going from generation 1 to 2.In other words, there exists a balance between binding interaction and sterichindrance that may optimize the GPx activity. And the linear polymer with thebiggest steric hindrance almost showed no GPx activity.In chapter Ⅳ, we have successfully synthesized a novel hyperbranchedpolyselenide with multi-catalytic sites at the branching units which acts as a novelglutathione peroxidase mimic. To the best of our knowledge, this may be the firstsuccessful example of incorporating catalytic sites onto the skeleton of thehyperbranched polymer. The initial reduction rate of using the hyperbranchedpolyselenides as the catalyst is around 4 times that of the comparative organicmonoselenide with similar structure, same selenium percent ratio and same massconcentration. By postsynthetic modification of the periphery this hyperbranchedpolyselenide could be solubilized in water, which may be very important for realuse as antioxidant drug. In this chapter we have also carried on the study ofhyperbranched oxindole with diselenide core which acting as a novel GPx mimic.Similar with the ester-peripheried dendrimer with diselenide core, the molecularstructure of the hyperbranched oxindole could afford proper microenvironment forthe catalysis, leading to the comparatively high GPx activity with the modelcompound. At the same mass concentration, the initial reduction rate of CuOOHof using hyperbranched oxindole with diselenide core as the catalyst is around 12fold that of the model compound. Because of the bio-and medical activity ofindole and its derivatives, the hyperbranched oxindole GPx mimic is expected tobe used as real antioxidant drug.