Design And Synthesis Of Four Coordinated Copper Ion Chelating Agent And Study On Chelation Selectivity

Disorders of metal ions in the body,especially copper ions,can lead to various diseases,such as Alzheimer’s disease,Parkinson’s disease,Wilson’s disease,Menkes disease,amyotrophic lateral sclerosis,etc.Therefore,the regulation of copper ion chelator is one of the important strategies for developing therapeutic drugs for these diseases.Based on the strategy of regulating the copper ion disorder in the AD brain,our group designed and synthesized a series of four-coordinate metal ion chelating agents with good copper ion selectivity.This thesis intends to build on the original research of this research group,using 8-aminoquinoline as the parent,introduce different chelating factors,and by changing the chelating factor of the side chain of the chelating agent,and by changing the electronic structure of the parent,A series of new four-coordinate 8-aminoquinoline copper ion chelating agents were designed and synthesized,and the structure-activity relationship of the chelating agent and the selectivity to copper ions were studied.In this thesis,the UV titration method is used to study the complexing ability of the new chelating agent and its selectivity with copper and zinc ions in detail.The results show that there are obvious differences in the ability of various heteroatoms to participate in the complexation.Among them,the introduction of nitrogen atoms in the side chain end groups is beneficial to the complexation of copper ions and the selectivity to copper and zinc ions.Its nucleophilic constant with copper is 15.2(TDMQ46),and the nucleophilic constant for zinc is 3.4,which is a difference 11.8 orders of magnitude.Correspondingly,the introduction of oxygen and sulfur atoms into the side chain end groups is not conducive to the complexation of copper ions and the selectivity to copper and zinc ions.Their nucleophilic constant with copper ions is the highest 5.8(TDMQ42),which is nucleophilic to zinc The constant is 2.6,which is 3.2 orders of magnitude difference.In addition,changing the electronic structure of the parent body,introducing chelating factors of different structures,and changing the quinoline ring to the phenanthroline ring will greatly affect the chelating agent’s ability to complex copper ions and the selectivity of copper and zinc ions.Copper ions are hardly complexed.The structure-activity relationship indicates that the type and spatial structure of the chelating factor will have a greater impact on the complexing ability of the compound with copper ions.Compounds TDMQ44 and TDMQ46 have the best copper ion chelating ability and copper-zinc ion selectivity in this series.Therefore,further investigations are carried out to explore whether they affect the homeostasis of other metals and whether they affect the functions of other metalloproteins/enzymes.The results show that the above compounds have no effect on tyrosinase and vitamin B12.In this thesis,based on the research of copper ion chelating agents in the early stage of the research group,a series of new types of copper ion chelating agents with four coordinations were designed and synthesized,and a series of compounds with different chelating factors and related copper and zinc ions were obtained.Chelating ability and selectivity,and screening the effects of some compounds on the steady-state balance of other metals,providing a certain degree of structure-activity relationship and theoretical basis for the subsequent design and synthesis of copper ion chelating agents with high selectivity and good chelating performance.And for the future to be further used as a copper ion chelating agent to carry out various screening experiments related to metal ion regulation and provide experimental basis.