靶向淀粉样蛋白AD分子探针生物活性的研究

发布时间：2018-06-25 16:47

本文选题：阿尔茨海默病 + β-淀粉样蛋白　；参考：《合肥工业大学》2012年硕士论文

【摘要】：阿尔茨海默病（AD）是一种严重危害人类健康的神经退行性疾病。在该病的治疗过程中，晚期治疗基本无效，早期治疗可以改善病症改变病程，所以建立一种高效灵敏的诊断技术有重要意义。阿尔茨海默病的病理特征主要有在大脑皮层和海马区出现了β-淀粉样蛋白（Aβ）聚集形成的老年斑（senile plaque，SP）和Tau蛋白过度磷酸化形成的神经纤维缠结(neurofibrillary tangles，，NFT)，其中Aβ的沉积形成老年斑被普遍认为是AD发病的中心环节，因而，靶向Aβ蛋白的分子影像剂对AD的诊断具有重要意义。 1、分子影像剂的设计：针对发病机理中重要病理改变之一的β-淀粉样蛋白及其沉积形成的老年斑作为靶点，基于天然产物选取三种主体骨架结构，以及三种中间连接键（Linker），通过计算机辅助设计分子对接法对分子结构进行了筛选和分析，最终选择了苯并噻唑席夫碱类化合物。 2、化合物的合成：设计合成路线，并对化学反应条件进行优化，合成目标化合物，并通过核磁共振1H谱（~1H-NMR）及红外（IR）对所合成化合物进行结构表征。 3、化合物的结合力分析：分别用受体的放射性配基结合试验（RadioligandBinding Assay of Receptor， RBA）和表面等离子共振法（Surface PlasmonResonance，SPR）考察、分析化合物与Aβ的结合特性。RBA结果显示，化合物3a较佳（K_i值：4.38nM），化合物3c（K_i值：10.82nM）、3f（K_i值：34.72nM）次之。SPR分析结果为化合物3f最好（K_D值：10.48nM），其次为化合物3a（K_D值：379.7nM）。计算机辅助设计分子对接结果证明，供电基有助于小分子化合物与Aβ的结合。AD人脑石蜡切片试验显示化合物3a与老年斑结合力良好。
[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.
【学位授予单位】：合肥工业大学
【学位级别】：硕士
【学位授予年份】：2012
【分类号】：R749.16;R96

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