Study On Synthesis Of Anti-Alzheimer's Disease Metal Chelator

ObjectiveAlzheimer's diease is a kind of central nerve system recessive disease,clini cally characterized by progressive memory loss and cognitive function decline.T his disease is usually cared with acetycholine-esterase inhibitors,which are of li mit benefit to most patients.One of AD's main symptoms is the amyloid cascad e around nerve cells,which is initiated when large transmembrane protein APP i s sequentially cleaved byβ-proteases andγ-secretase and the fragments aggreg ates.Zn and glycosaminoglycans as imporntant cofactors are proposed to enhanc e this process.Also,Zn plays an important role in oxidation in AD.Based on all above,Zn is a potential target of AD.Using metal chelator is one of the m ethods to modulate Zn content in human bodies.BAPTA is a kind of metal che lator developed from EGTA,without the drawbacks such as:insufficient selectivi ty against competing cations;particularly H⁺ and Mg²⁺,complex stoichiometries of interaction with Ca ²⁺;inflexibility of molecular design,or the difficulty of rationally adjusting indicator properties by tinkering with the molecular structure.BAPTA cannot pass through membrane,so it's of great necessity to change its structure to improve its lipophilicity,such as BAPTA-AM,Dp99 with a oc tenol on each side,and Dp109 with a.cetanol on each side.In order to discuss how side chains effect chelating effect of this kind of compound we design dif ferent substituted derevatives of side chains.In this article,a derivative with eth ylene glycol mono cetanyl ether as side chain was totally synthesized according to the references to optimized synthesis method,to develop synthesizing process, and to provide basis for subsequent studies.Method1,2-bis(2-nitrophenoxy)ethane was synthesized by the reaction of 2-nitrophen oxide and 1,2-dibromoethane;1,2-Bis(2-nitrophenoxy)ethane was gotten by the re duction catalyzed by CuSO₄ and NaBH₄;1l,2-bis(2-aminophenoxy)ethan(BAPTA-E M) was yielded through the reaction with ethyl bromoacetate catalyzed by 1,8-bi s(dimethylamino)naphthalen and Nal;BAPTA was gotten by the hydrolysis reacti on in ethanol with KOH and then dehydrating with acetic anhydride and pyridin e to yield BAPTA anhydride;target compoud was synthesized by esterification r eaction catalyzed by NaH.We use CuSO₄ and NaBH₄ instead of H₂-Pd to reduc e nitro;NaH instead of Na to catalyze the reaction of glycol and in the final st ep get target compound with NaH to catalyze.ResultWe summarized the chemical synthesis method formerly and made a in-dept h discussion of the synthesis technology of the BAPTA derivatives.According to the structure activity relationship,we designed and synthesized the target comp ound.ConclusionSome BAPTA derivatives were obtained in this experiment by convenient a nd feasible methods.The methods of nitro reduction;ether synthesis with NaI;a nd esterification with NaI as catalyst were discussed.