【摘要】：阿爾茨海默癥(Alzheimer’s Disease,AD),最常見的癡呆類型,是一種慢性神經(jīng)退行性疾病,其臨床特征表現(xiàn)為記憶損傷,認(rèn)知復(fù)雜,語言障礙,情緒不穩(wěn)和行為異常等。乙酰膽堿(Acetylcholine,ACh)和?淀粉樣蛋白(Amyloid?-protein,A?)沉積水平在AD的發(fā)生、發(fā)展過程中起重要作用。雖然AD的發(fā)病機制尚未完全了解,目前認(rèn)為AD的最有效的治療方法是增強大腦中的膽堿能神經(jīng)傳遞并降低ACh水解;另外,保護(hù)神經(jīng)細(xì)胞免受Aβ誘導(dǎo)的細(xì)胞損傷和凋亡,對預(yù)防及治療AD也具有積極的作用。相對于單靶點藥物,多靶點藥物可針對疾病的不同生理環(huán)節(jié)發(fā)揮作用并且具有不良反應(yīng)少、臨床使用劑量低、療效顯著等優(yōu)點。本課題把結(jié)構(gòu)骨架新穎且具有較好乙酰膽堿酯酶抑制活性的三氮唑化合物MX-1作為先導(dǎo)化合物,對其進(jìn)行結(jié)構(gòu)修飾合成了一批衍生物。然后我們對目標(biāo)化合物做了相關(guān)體外活性測試,得到具有潛在抗AD活性的化合物39:該化合物對AChE表現(xiàn)出較強的抑制作用,IC50為7.23μM;對Keap1-Nrf2蛋白相互作用具有一定的抑制活性;對A?25-35誘導(dǎo)的神經(jīng)細(xì)胞SH-SY5Y損傷具有較好的保護(hù)活性,濃度在10μM時,細(xì)胞存活率達(dá)到了96.5%;對正常細(xì)胞系(HaCaT細(xì)胞系和NIH-3T3細(xì)胞系)沒有明顯的細(xì)胞毒作用;虛擬對接表明,該化合物與AChE活性位點氨基酸殘基具有很好的結(jié)合作用;物化性質(zhì)預(yù)測表明該類化合物具有合適的透過血腦屏障能力。本課題為設(shè)計高效、低毒的新型多靶點抗AD藥物提供分子模型和理論依據(jù),對研發(fā)出有效的抗AD藥物具有十分重要的意義,值得繼續(xù)深入研究。
[Abstract]:Alzheimer's disease (Alzheimer's Disease,AD), the most common type of dementia, is a chronic neurodegenerative disease characterized by memory impairment, cognitive complexity, language disorders, emotional instability and behavioral abnormalities. Acetylcholine (Acetylcholine,ACh) and? Amyloid protein (Amyloid?-protein,A?) Sedimentary level plays an important role in the occurrence and development of AD. Although the pathogenesis of AD has not been fully understood, it is believed that the most effective treatment for AD is to enhance cholinergic nerve transmission in the brain and reduce ACh hydrolysis. In addition, protecting neurons from A 尾 -induced cell damage and apoptosis also plays an active role in the prevention and treatment of AD. Compared with single target drugs, multi-target drugs can play a role in different physiological aspects of disease and have the advantages of less adverse reactions, low clinical dosage and remarkable curative effect. A series of derivatives were synthesized by structural modification of triazole compound MX-1, which has novel structure skeleton and good inhibitory activity of acetylcholinesterase. Then we tested the activity of the target compound in vitro and got the compound 39 with potential anti-AD activity. The compound showed a strong inhibitory effect on AChE, IC50 was 7.23 渭 m; It has a certain inhibitory activity on the interaction of Keap1-Nrf2 protein and a good protective activity against the SH-SY5Y damage induced by AZ25-35. The survival rate of the cells reached 96.5when the concentration of 10 渭 M was 10 渭 M. There was no obvious cytotoxic effect on normal cell line (HaCaT cell line and NIH-3T3 cell line), and virtual docking showed that the compound had a good binding effect with the amino acid residues of AChE active site. The prediction of physicochemical properties indicates that the compounds have the appropriate ability to penetrate the blood-brain barrier. This paper provides a molecular model and theoretical basis for the design of new multi-target anti-AD drugs with high efficiency and low toxicity. It is of great significance for the development of effective anti-AD drugs and is worthy of further study.
【學(xué)位授予單位】：濟(jì)南大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R914;R96

【參考文獻(xiàn)】

相關(guān)期刊論文 前1條

1 應(yīng)俠;吳振;雷嚴(yán);王立強;;阿爾茨海默病的發(fā)病機制及治療藥物研究進(jìn)展[J];中國藥房;2014年33期

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本文編號：2420451