Design,Synthesis And Biological Activity Evaluation Of New Titronyl Nitroxide Radicals And Schiff Bases Derivatives

Background:With the development of nuclear energy technology and its application,the potential risk of suffering radiation damage is also greatly increased.Radiation damage can be induced by the exposure of radiation accidents,or participating in some activities,such as space exploration,radiation therapy,radiation products processing and so on.Acute radiation syndrome(ARS),also known as radiation toxicity,is a collection of severe health effects when people are present within short-time exposure to high amounts of ionizing radiation.When it comes to the radiation accident,cancer treatment and diagnostic radiology,high doses of radiation can lead to acute radiation syndrome,seriously affecting the nervous system,blood vascular system,hematopoietic and gastrointestinal system.To prevent and reduce the harm of radiation accident to human health,many scientists have dedicated themselves to screening safe and effective radioprotective drugs and researching radioprotection and controlling measures.Fortunately,some identified compounds,natural products and biological agents have proved effective in radioprotection.Among them,the representative Drug Amifostine(WR-2721)which contains thiol group has been approved by the United States Food and Drug Administration(FDA)to be used for the prevention of radiotherapy for tumor patients,but its severe side effects limit further use of amifostine in clinic.Biological macromolecules such as DNA,protein and lipid can be damaged by free radicals induced by radiation,but in the meantime,nitroxide radicals have been proved to have significant radical scavenging ability.Therefore,based on the previous work,we have designed and synthesized two series of nitroxide radical derivatives,in order to obtain the optimal effective compounds for further research on low toxicity radioprotective drugs.Schiff base,is a kind of compounds with the general structure R2C=NR’,and the solitary electrons offered by N atom on its hybrid orbit endows it with important chemical and biological significance.Schiff base has been identified to have powerful antibacterial,sterilization,antitumor and antiviral properties.Therefore,a series of schiff base were synthesized and investigated their antibacterial effects in order to obtain new leading compound with higher antibacterial activity.Objective:Two series of nitroxide radical compounds were synthesized,and their antioxidant activity and radioprotective effect were tested,in order to get the leading compound for further research and development of high-efficiency radioprotective drug.Twenty-one schiff bases were synthesized in our previous works,and their antibacterial effect were investigated in order to find a good compound with high antibacterial activity.Method:Imidazoles nitroxide radical compounds were synthesized from different aldehyde and double hydroxylamine.Tempol nitroxide radical compounds were also synthesized from various phenolic acids and tempol as starting materials.The structures of these synthesized compounds were confirmed by MS,IR and EPR.The ability of scavenging free radicals of the imidazoles nitroxide radical compounds were evaluated with the DPPH radical scavenging activity experiments.The protective effect of the compounds on oxidative damage induced cellular injury in vitro were evaluated with the protection of H2O2 induced cellular oxidative experiments.And the protective effect of nitroxide radical compound N5 on radiation caused cellular damage were also evaluated.The bacteriostatic activity of the synthesized schiff base were evaluated with the broth dilution method.Results:In this paper,15 kinds of nitroxide radical compounds N1-N12 and T1-T3 were studied.The spectrum experiments verified the structures of all synthesized compounds were identified.The DPPH radical scavenging activity experiments showed that nitroxide radical compounds N3,N4,N5 and N6 have better radical scavenging ability than the positive control Tempol.The protection of H2O2 induced cellular oxidative damage experiments indicated that N5 showed better oxidative damage protective effect both on L-02 cells and HepG-2 cells.The protection of radiation injury researches showed that using gamma ray to irradiate,N5 can get the radiological protection effect under 4 Gy dose.The broth dilution experiment showed that schiff base S5 has better antibacteral activity on the four tested strains comparing with other compounds.Conclusion:In this thesis,fifteen nitroxide radical compounds were designed and synthesized.The DPPH radical scavenging activity,the protection of hydrogen peroxide induced cellular oxidative damage and the protection of radiation injury researches were carried out to evaluate the biological activities of these compounds.The results showed that nitroxide radical compound N5 has better free radicals scavenging activity and radioprotective effect,which was the best candidate for further study.The antibacterial experiments of twenty-one schiff base compounds indicated that schiff base S5 has shown better antibacterial effect,which could be a good foundation for further antibacterial drug research.