Synthesis And Chelation Selectivity Of 8-Aminoquinoline Chelating Agents

Oxidation-reducing metal ion disorders（especially copper ions disorder）in the brain of patients with Alzhelmer’s disease（AD）are the main factors of oxidative stress in AD brain.Therefore,the development of selective copper ion chelating agents to restore the steady state balance of ions in the brain will provide an important basis for the development of AD drugs.This paper is based on the research direction of this group to develop a highly selective copper ion chelating agent“TDMQ”（TetraDentate MonoQuinoline）AD drug candidate by introducing an electron donating group and a modified quinoline ring on the TDMQ compound quinoline ring.The length of the side chain is to improve the structure-activity relationship of the TDMQ series of compounds.Wherein,a compound containing a weak electron-donating group methyl group TDMQ14,15 is obtained by introducing different electron-donating groups and changing the position of the group on the quinoline ring;a compound containing a strong electron-donating group methoxy group TDMQ31,32,33 and N,N-dimethyl-containing TDMQ38,39.Chelating selectively studies on synthetic compounds.The results show that the nucleophilic constant of the TDMQ with electron donating group and the copper ion’s log Kapp^{[Cu（II）-TDMQ]}≥14.0;and its selectivity to copper and zinc ions is more than 5 orders of magnitude,highest to 12.2 orders.On the other hand,by comparing the position of the quinoline ring C2 with the proximal N-chain of the side chain,a methylene group and two methylene chelate selectivity differences were investigated.The results show that the 8-aminomonoquinoline compound and TDMQ having two mrthylene groups between the C2 position of the quinoline ring and the N atom of the proximal chain of the side chain exhibits good chelation selectivity for copper ions.In addition,in order to further explore the mechanism of action of TDMQ series of compounds,This paper conducted an in-depth study on the effects of the lead compounds TDMQ20 and TDMQ22 on the activity of metal ion-containing active enzymes in vivo.The results show that TDMQ20 and TDMQ22 do not affect the activity of copper ionase present in the body at high molar concentrations,which proviede experimental basis and theoretical basis for the synthesis of metal ion chelating agent with good selectivity.