天然产物姜黄素的结构改造及生物活性的研究

发布时间：2018-04-18 23:19

本文选题：天然产物 + 姜黄素　；参考：《合肥工业大学》2016年硕士论文

【摘要】：天然产物姜黄素具有抗氧化、抗肿瘤、抗炎、神经保护和抗阿尔茨海默病等多种生物活性,但因为自身结构稳定性较差,生物利用度低,限制了其临床应用。阿尔茨海默病(AD)是一种慢性神经退行性疾病,p-淀粉样蛋白(Aβ)的聚集形成老年斑(senile plaque, SP)是AD的典型病理学特征之一。因此,发展靶向p-淀粉样蛋白的小分子探针,结合现代影像技术,对AD患者进行早期诊断,具有非常重要的意义。本论文利用姜黄素的自身生理活性优势,进行适当的结构改造得到系列姜黄素类似物,筛选可用于AD早期诊断的靶向老年斑的分子探针。(1)对姜黄素进行双羰基结构的改造,利用计算机辅助分子设计,并结合相关参考文献,进行综合筛选,确定所设计的姜黄素类似物。(2)参考相关文献,确定目标化合物的合成路线,在合适的实验条件下对目标化合物2a-2c和4a-4g进行合成、分离和纯化,并且用核磁共振对化合物进行结构表征。(3)通过受体的放射性配基结合分析(RBA)实验对所设计的姜黄素类似物进行结合力的测定,筛选出一些与靶点蛋白结合活性较高的小分子化合物。从实验结果可以看出化合物2c、4a、4d、4f和4g等与受体蛋白Aβ有较优的结合力。AD脑组织切片荧光染色实验表明化合物4d与老年斑结合良好,具有较高的特异性。对化合物4g进行生物学在体分布实验,考察了4g在主要脏器不同时间点的分布情况,通过实验结果可以看出药物可以透过血脑屏障,同时还有着较高的脑摄取率和适当的脑清除率,符合阿尔茨海默病分子探针药代动力学的要求。(4)在之前的研究基础上,结合文献报道,设计出含氟的姜黄素类似物以期用作磁共振显像小分子探针,实验结果表明,小分子可以通过血脑屏障,但RBA实验结果表明化合物与Ap的结合力较弱,有待进一步改进。
[Abstract]:Curcumin has many biological activities, such as antioxidation, anti-tumor, anti-inflammation, neuroprotection and anti-Alzheimer 's disease, but its clinical application is limited because of its poor structural stability and low bioavailability.Alzheimer's disease (AD) is a chronic neurodegenerative disease, pamyloid A 尾 (A 尾) agglomeration and formation of senile plaque plaque (SPV) is one of the typical pathological features of AD.Therefore, the development of small molecular probes targeting p- amyloid protein, combined with modern imaging technology, for early diagnosis of AD patients, is of great significance.In this paper, a series of curcumin analogues were obtained by using the advantage of curcumin's own physiological activity, and a series of curcumin analogues were obtained by structural modification. The dicarbonyl structure of curcumin was modified by screening the molecular probe, which could be used for the early diagnosis of AD.By using computer-aided molecular design and combined with related references, the synthetic route of the target compounds was determined by comprehensive screening to determine the references of curcumin analogue.The target compounds 2a-2c and 4a-4g were synthesized, separated and purified under suitable experimental conditions.The structure of the compound was characterized by nuclear magnetic resonance (NMR). The binding capacity of the designed curcumin analogues was determined by radioligand binding assay (RBA).Some small molecular compounds with high binding activity to target proteins were screened out.It can be seen from the experimental results that compound 2cx4a1, 4d, 4f and 4g have better binding power with receptor protein A 尾. The fluorescence staining experiment of AD brain tissue section shows that the compound binds well to senile spot for 4 days and has high specificity.In vivo biological distribution of compound 4 g was studied. The distribution of 4 g at different time points in main organs was investigated. The results showed that the drug could penetrate the blood-brain barrier.There are also high brain uptake rates and appropriate brain clearance rates, which meet the requirements of pharmacokinetics of molecular probes for Alzheimer's disease.Curcumin analogue containing fluorine was designed to be used as a small molecular probe in magnetic resonance imaging. The experimental results showed that the small molecule could pass through the blood-brain barrier, but the RBA results showed that the binding force between the compound and AP was weak, which needed to be further improved.
【学位授予单位】：合肥工业大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：TQ460.1;O629

【相似文献】