本文選題：阿爾茨海默病 + β-淀粉樣蛋白��； 參考：《合肥工業(yè)大學(xué)》2012年碩士論文

【摘要】：阿爾茨海默�。ˋD）是一種嚴(yán)重危害人類健康的神經(jīng)退行性疾病。在該病的治療過程中，晚期治療基本無效，早期治療可以改善病癥改變病程，所以建立一種高效靈敏的診斷技術(shù)有重要意義。阿爾茨海默病的病理特征主要有在大腦皮層和海馬區(qū)出現(xiàn)了β-淀粉樣蛋白（Aβ）聚集形成的老年斑（senile plaque，SP）和Tau蛋白過度磷酸化形成的神經(jīng)纖維纏結(jié)(neurofibrillary tangles，，NFT)，其中Aβ的沉積形成老年斑被普遍認(rèn)為是AD發(fā)病的中心環(huán)節(jié)，因而，靶向Aβ蛋白的分子影像劑對AD的診斷具有重要意義。 1、分子影像劑的設(shè)計(jì)：針對發(fā)病機(jī)理中重要病理改變之一的β-淀粉樣蛋白及其沉積形成的老年斑作為靶點(diǎn)，基于天然產(chǎn)物選取三種主體骨架結(jié)構(gòu)，以及三種中間連接鍵（Linker），通過計(jì)算機(jī)輔助設(shè)計(jì)分子對接法對分子結(jié)構(gòu)進(jìn)行了篩選和分析，最終選擇了苯并噻唑席夫堿類化合物。 2、化合物的合成：設(shè)計(jì)合成路線，并對化學(xué)反應(yīng)條件進(jìn)行優(yōu)化，合成目標(biāo)化合物，并通過核磁共振1H譜（~1H-NMR）及紅外（IR）對所合成化合物進(jìn)行結(jié)構(gòu)表征。 3、化合物的結(jié)合力分析：分別用受體的放射性配基結(jié)合試驗(yàn)（RadioligandBinding Assay of Receptor， RBA）和表面等離子共振法（Surface PlasmonResonance，SPR）考察、分析化合物與Aβ的結(jié)合特性。RBA結(jié)果顯示，化合物3a較佳（K_i值：4.38nM），化合物3c（K_i值：10.82nM）、3f（K_i值：34.72nM）次之。SPR分析結(jié)果為化合物3f最好（K_D值：10.48nM），其次為化合物3a（K_D值：379.7nM）。計(jì)算機(jī)輔助設(shè)計(jì)分子對接結(jié)果證明，供電基有助于小分子化合物與Aβ的結(jié)合。AD人腦石蠟切片試驗(yàn)顯示化合物3a與老年斑結(jié)合力良好。
[Abstract]:Alzheimer's disease (AD) is a neurodegenerative disease that seriously endangers human health. In the course of the treatment of the disease, the late treatment is basically ineffective, early treatment can improve the course of the disease, so it is important to establish a highly effective and sensitive diagnostic technique. The pathological features of Alzheimer's disease are mainly 尾 -amyloid protein (A 尾) aggregation in cerebral cortex and hippocampal area, senile plaqueus SP and neurofibrillary tangles formed by excessive phosphorylation of Tau protein, in which A 尾 is deposited. Senile plaques are generally considered to be the central link in the onset of AD. Therefore, molecular imaging agents targeting A 尾 protein are of great significance for the diagnosis of AD. 1. Design of molecular imaging agents. Based on the selection of three main skeleton structures and three intermediate bonding bonds (Linker) of natural products, the molecular structure was screened and analyzed by computer aided design (CAD) molecular docking method. Finally selected benzothiazole Schiff base compound. 2. Synthesis of compounds: design the synthetic route, and optimize the chemical reaction conditions to synthesize the target compound, The structures of the synthesized compounds were characterized by 1H NMR and IR spectra. 3. The binding ability of the compounds was studied by radioligand binding Assay of the receptor (RBA) and surface plasmon resonance (SPR). Analysis of binding properties of compounds with A 尾 .RBA results showed that compound 3a was the best (Kstui value: 4.38nM), compound 3c (Ki value: 10.82nM) and compound 3f (Ki value: 34.72nM) followed by compound 3f (KD value: 10.48nM), followed by compound 3a (KD value: 3.379.7nM). The results of molecular docking with computer aided design showed that the power supply group was helpful to the binding of A 尾 with small molecular compounds. The results of paraffin section test showed that compound 3a had good binding power to senile spot.
【學(xué)位授予單位】：合肥工業(yè)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2012
【分類號(hào)】：R749.16;R96

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