Synthesis Of Functional Polymers Via The Biginelli Multicomponent Reaction And The Study Of Properties

Oxidative stress leads to disrupted redox signaling and/or oxidative damage to cell and tissue,which is believed to be closely related to aging and several degenerative diseases.Antioxidant supplementation is regarded as the most direct way to deal with oxidative stress.Although small molecule antioxidants that are naturally extracted or synthetic show good performance in the in vitro experiments and in vivo oxidative damage model experiments.The basic properties of these antioxidants(such as high instability,rapid clearance from the body,and poor water solubility)are the possible reasons for their low bioavailability,which may in turn explain their poor performances in suppressing the oxidative stress levels in patients.Thus,the development of new polymeric antioxidants that are safe and have clear effects in vivo,which can be easily dispersed in aqueous solutions with clearly enhanced stability,activity and bioavailability in vivo is important in terms of fundamental research and practical applications.The main research work includes the following parts:Firstly,a high throughput(HTP)method has been developed for monomers and corresponding polymers by carrying out the Biginelli reaction and free radical polymerization in an HTP manner.Using this method,five aldehydes extracted from essential oils were used to rapidly synthesize 25 monomers containing dihydropyrimidines(DHPM)group with high yields.The 25 corresponding polymers were conveniently prepared via mini-HTP radical polymerization.The distinct radical scavenging ability of these Biginelli polymers and monomers was evaluated through a HTP measurement.Three best radical scavengers were chosen and copolymerized with Poly(ethyleneglycol)methacrylate(PEGMA)via a convenient radical polymerization to produce the water-soluble and biocompatible copolymers.The cytotoxicity and ability to protect cells from UV damage of copolymers were evaluated.The copolymer using methylthiourea and benzaldehyde as raw materials had excellent cellular safety,while the copolymer from thiourea and benzaldehyde or methylthiourea and vanillin demonstrated moderate cytotoxicity.All of the three copolymers supplied cell-protection from the UV light,and the protection ability of the copolymer from methylthiourea and benzaldehyde was the best.The viability of A375 and L929 cells was 97% and 106% in the presence of this copolymer(10 mg/m L)after UV irradiation.This highlights the value of the Biginelli reaction and HTP methods to achieve new functional polymers.The screened copolymer has a great potential to become a new generation of sunscreen.Secondly,new copolymers were effectively prepared through post-polymerization modification(PPM)of the copolymer with the best radical scavenging ability synthesized by the above work.The resulting copolymers were fluorescent because of the heterocyclic structures generated by PPM;thus,the endocytosis of these copolymers could be easily detected by confocal laser scanning microscope(CLSM).The radical scavenging ability and protection to cells against oxidative stress of new copolymers was diminished.In contrast,the copolymers obtained by PPM method were superior to the original Biginelli-type copolymer in preventing UV-induced DNA damage and cell necrosis.This result indicates that the UV-protection of polymer is not completely consistent with its antioxidant ability,and the UV-protection mechanism of polymers is still vague.Thirdly,fluorescent copolymers containing both carbazole rings and DHPM group were synthesized via the Biginelli reaction using N-ethylcarbazole-3-carbaldehyde instead of benzaldehyde as the starting materials.The endocytosis of these copolymers could also be detected by CLSM.The antioxidant and UV-protective abilities of copolymers containing both carbazole or benzene rings and DHPM group were investigated.The copolymers containing C=O group exhibited weak antioxidant activities,while the copolymers containing C=S group were strongly antioxidant.However,all of the four copolymers effectively protected cells from the UV damage,suggesting the UV-prtection and antioxidatant properties of polymers are independent.According to the ELISA analysis results,the four copolymers containging DHPM group blocked the production of CPD-DNA and 6-4-PP-DNA,two major UV-induced damaged DNA in cells.A similar result was obtained in the isolated DNA model,furtherly indicating that the UV-protection mechanism of polymers containing DHPM group is to prevent UV-induced DNA damage.Last but not least,to increase the antioxidant ability of the polymers containing DHPM group,the ferrocene containing monomer was synthesized through the Biginelli reaction using ferrocenecarboxaldehyde as the starting materials.The corresponding water-soluble copolymer was conveniently prepared via radical polymerization.The ferrocene-DHPM copolymer demonstrated significantly better antioxidant ability than copolymers containing only ferrocene or DHPM groups alone.Moreover,the ferrocene-DHPM copolymer possessed excellent cellular safety and biosecurity.This copolymer offered much better protection to cells against tert-butyl hydroperoxide(t-BHP)induced oxidative stress than traditional small molecule antioxidants.In an in vivo mouse model experiment,this copolymer effectively counteracted CCl4-induced serious acute liver injury,the therapeutic effect was superior to that of silymarin,which is an active pharmaceutical ingredient in clinically prescribed medicines.These results demonstrate the combination of organometal compounds and multicomponent reactions(MCRs)as a powerful tool to exploite new functional polymers.The resulting copolymer product demonstrated good antioxidant ability,with a potential for in vivo applications to inhibit oxidative stress-induced damage.In summary,a series of safe and effective polymeric antioxidants and polymeric sunscreens has been developed via the Biginelli reaction.These polymers are easily accessible and biocompatible,with great potential to become therapeutic agents.This highlights the value of MCRs to achieve new functional polymers with useful properties.