Design And Synthesis Of Tetradendate Monoquinolines Copper Ion Chelators And The Study On Anti-oxidative Stress

Alzheimer's disease(AD)is one of the most common progressive neurodegenerative diseases,which is associated with memory impairment,agnosia,aphasia,executive dysfunction and personality and behavior change of comprehensive performance as the main characteristics of dementia and the pathology of AD still remain unclear.Abnormal concentration of transition metal ions,such as copper,iron,and zinc,leads to A? aggregation and the formation of ROS and H2O2 are beneficial for the damage of neuron and toxicity of neuronal cell by means of oxidative stress reaction.The homeostasis of metal ion plays a significant role in the pathogenesis of AD.CQ and PBT2,tested in the clinical trial as metal ion chelators,were abandoned due to lacking of selectivity for copper and strong affinities with zinc,which led to disruption of zinc and toxicity of neuron.Therefore,it is very important to develop the specific copper ion chelators as the potential drug for the treatment of AD.Based on the previous research in our group,a series of tetradentate mono(8-amino or 8-hydroxy)quinolines copper ion chelators are designed and synthesized by means of introducing aliphatic flexible chain at the proximal part on C2 position of the quinoline ring.The affinity constants,the stoichiometries and selectivity of these chelators for copper and zinc are determined by UV titrations.The results show that the affinity constants of these series of compounds are in the rang from 8 to 10,which exhibits no big difference from the affinity constant between copper and A? and can not meet the demand for the potential anti-AD drug.Meanwhile,the structure-activity relationship are determined via introducing different substituents on the quinoline ring and measured by the affinity constant between chelator and copper.The results show that(1)quinoline ring with one electron withdrawing substituent,or two electron withdrawing substituents,or amino group(hydroxy group)on th C8 position show less of an effect on the affinity constant between chelator and copper;(2)these metal ion chelators have an affinity constant for copper that is 4 orders of magnitude higher than that of chelators with electron withdrawing substituents,but the affinity constant for zinc,in the rang of 8.5-9.4,is higher than that of zinc with human serum albumin(HSA),leading to the disruption of zinc.To solve the problem of low affinity constant for these chelators with copper,a new series of tetradentate mono(8-amino)quinoline were designed and synthesized by increasing the length of side chain at the proximal part on the C2 position of the quinoline ring.The affinity constants,the stoichiometries and selectivity of the new series of chelators for copper and zinc are determined by UV titrations.The results show that these new series of chelators have an affinity constant for copper that is 5 orders of magnitude higher than that of chelators discussed above,and the affinity constant for zinc is lower than that of zinc with HSA,which is suggesting that the new series of tetradentate mono(8-amino)quinolines exhibit excellent selectivities and strong affinities for copper.TDMQ-20,one of the new series of tetradentate mono(8-amino)quinolines selected as the leading metal ion chelator,is used for study on anti-oxidative stress in vitro in this paper.The results show that TDMQ-20 is able to fully abstract Cu2+ from Cu2+-A?1-16 even in the presence of 3 molar equivalent of zinc and subsequently generate the Cu2+-TDMQ-20 complex.Upon reduction of the complex by 100 molar equivalent of GSH,copper is easily released from TDMQ-20 and transferred to the copper-carrier proteins,which are the integrant of copper at the physiological pH.The ability to inhibit the formation of oxidative stress is measured via the asorbate consumption of A?1-16-metal ion and metal-TDMQ-20 as an indirect evaluation.The results show that 1 molar equivalent of TDMQ-20 is able to inhibit the formation of oxidative stress even in the presence of 100 molar equivalent of zinc induced by Cu2+-A?1-16.Up to now,the pharmacology of TDMQ-20 is under investigation.In this paper,based on monoquinoline as the general structure,a series of tetradentate mono(8-amino)quinoline copper chelators were synthesized.And the specific copper ion chelator was selected to be used for research of anti-oxidative stress in vitro.These studies provided theory evidence and estabilished foundation to devolop specific copper ion chelatorsasthe potentialdrug for anti-AD.