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Study on Synthesis of Anti-Alzheimer’s Disease Metal Chelator

Author: FuYingBo
Tutor: HuangXueShi
School: China Medical University
Course: Pharmaceutical Analysis
Keywords: BAPTA Anti - Alzheimer's Metal ions of sodium borohydride Reduction of the nitro Sodium hydride
CLC: R914
Type: Master's thesis
Year: 2009
Downloads: 155
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Abstract


The purpose of dementia (Alzheimer'S disease, AD) is a degenerative disease of the central nervous system (CNS), the clinical manifestations of progressive memory loss and cognitive decline. The major clinical use of acetylcholinesterase inhibitors to treat this disease, but for most patients the effect is not ideal. One of the main symptoms of AD amyloid plaques in the outer periphery of the nerve cells, these plaques are large protein molecules across the cell membrane capacity APP the enriched β protease and γ-secretase cleavage peptide fragments formed, zinc ion and mucopolysaccharides and other auxiliary factor in this process plays an important role in promoting. In addition, the zinc ion in the process of cell oxidative damage in AD disease also plays an important role, and therefore the zinc ion has become the potential target of the treatment of AD disease. Use the metal ion chelator means of precisely adjust the concentration of zinc ions in the body. BAPTA is a development on the basis of of EGTA, a metal ion chelating agent, which overcomes the front of a chelating agent for the competing cations, particularly hydrogen ions and magnesium ions low selectivity, stoichiometric complex, chemical structure is complex, and thus difficult rely on changing the structure change chelating characteristics shortcomings. Meanwhile, BAPTA with UV absorption, fluorescence monitoring is also available, and can even be used as a visual indicator. BAPTA itself does not pass through the cell membrane, so its structure is modified to increase the fat-soluble. Representative of its methyl ester BAPTA-AM and on each side of a carboxyl group connected to an n-octanol of Dp99 and 18 alkyl side chains Dp109. To discuss the impact of side chain to replace the base of these compounds by chelation, we intend to design the side chain base derivatives to find efficiency and low toxicity anti-Alzheimer active pharmaceutical lead compounds. This thesis is mainly derivatives of ethylene glycol monomethyl ether 16 Total Synthesis of its side chain, exploring these compounds synthesis methods, and appropriate technology, experimental basis for subsequent structure-activity relationship analysis. Pro-nitrophenol and 1,2 - dibromoethane as raw materials the reaction of 1,2 - (bis 2 - nitrophenyl) ethane, and then through the copper sulfate - sodium borohydride, catalytic reduction of the nitro give 1 of potassium hydroxide in alcohol, 2 - (bis 2 - aminophenol) ethane, 1,8 - dimethylnaphthalene and sodium iodide catalyzed with ethyl bromoacetate to generate the BAPTA ethyl (BAPTA-EM); aqueous solution obtained by hydrolysis BAPTA; acetic anhydride pyridine dehydration BAPTA anhydride; anhydride with a side generated by the ethylene glycol and bromohexadecane glycol monoethyl XVI ether was obtained by the catalytic reaction of the sodium hydride the BAPTA glycol of ether . In this experiment, we used copper sulfate - sodium borohydride substituted hydrogen - palladium on carbon reduction of the nitro group reduction method, improve the security of the experiment; using sodium hydride to replace sodium to catalyze ethylene glycol sixteen ether reaction , increase the reaction yield; final step, according to the literature method used directly sixteen anhydride and ethylene glycol monomethyl ether reaction failed to give the product, we use tetrahydrofuran as the solvent, sodium hydride, to catalyze the esterification reaction has been successful. Results of the experiments reported in the literature synthesis method based on the synthesis process of BAPTA and its derivatives in-depth exploration of, and in accordance with the structure-activity relationship analysis, design synthesis route completed BAPTA glycol 16 Ethers . Conclusion The synthesis method is simple and feasible, BAPTA glycol sixteen ether synthesis. Paper, copper sulfate - sodium borohydride reduction of the nitro group; catalytic sodium hydride ether synthesis; sodium hydride to catalytic esterification reaction.

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