中文摘要
阿尔茨海默病(AD)是严重威胁人类健康和生活质量的重要疾病之一，目前尚无特效治疗或逆转其进展的药物。实验研究已证实神经生长因子(NGF)极有可能成为治疗AD等神经退行性疾病的重要药物，但由于NGF是一类蛋白，它的蛋白特性(如抗原性，不能通过血脑屏障等)限制了它的临床应用，因此，从天然产物中寻找具有类似NGF功能的小分子化合物具有重要意义。前期研究表明川楝子的总提物具有与NGF类似的活性，可以诱导神经细胞分化。在对川楝子的化学成分进行活性追踪分离研究中，我们发现了三个柠檬苦素类化合物具有明显的诱导神经细胞分化活性。本课题拟通过放大药材量来富集一定量的活性化合物24并对其进行结构修饰，寻找高活性化合物，探讨其构效关系，为开发防治AD等神经退行性疾病的药物奠定基础。
英文摘要
Alzheimer’s disease (AD) is one of the major diseases that threaten human health and quality of life seriously and there is no effective treatment at present. Experimental studies have confirmed that nerve growth factor (NGF) is very likely to become important drugs for treatment of neurodegenerative diseases such as AD. But because of the NGF is a class of proteins, its protein characteristics (such as antigenicity, cannot pass the blood-brain barrier,etc.) limit its clinical application. Therefore, looking for some small molecule compounds that have the function similar to NGF from the natural products is of great significance. Earlier research showed that a crude extract of the fruits of Melia toosendan had the activity similar to NGF and it could induce neuronal differentiation. We have taken the activity-tracking study on the chemical constituents of M. toosendan and three limonoids have been found to induce neuronal differentiation significantly. In this project, the fruits of M. toosendan (100Kg) will be investigated to enrich the amount of the active compound 24. Then we will study on the structure modification of the active compound 24 to find the more active compounds and investigate its structure-activity relationship. Therefore, this project will lay the foundation for the development of drugs for prevention and treatment of neurodegenerative diseases such as AD.
结题摘要
阿尔茨海默病(AD)是严重威胁人类健康和生活质量的重要疾病之一，目前尚无特效治疗或逆转其进展的药物。实验研究已证实神经生长因子(NGF)极有可能成为治疗AD等神经退行性疾病的重要药物，但由于NGF是一类蛋白，它的蛋白特性(如抗原性，不能通过血脑屏障等)限制了它的临床应用，因此，从天然产物中寻找具有类似NGF功能的小分子化合物具有重要意义。我们在前期工作中发现川楝子的总提物具有与NGF类似的活性，可以诱导神经细胞分化,并且在对川楝子的化学成分进行活性追踪分离研究中发现了四个柠檬苦素类化合物具有明显的诱导神经细胞分化活性。本课题在前期工作基础上进一步对川楝子200 Kg进行系统的化学成分研究，从中分离鉴定了33个柠檬苦素类化合物，其中5个为新化合物；确定了川楝素的绝对构型24,25,26,27-tetra-norapotirucalla-3α,12α-diacetoxy-1α,7α,29α-trihydroxy-20,22-dien-14β,15β:21,23:19,29β-triepoxy-11-one (1S,3R,4R,7R,8S,10S,12R,13R,14S,15R,17R,29R)和川楝素的互变异构体的结构；对活性化合物24进行结构修饰，发现在其3位引入烟酰基后其诱导神经细胞分化活性明显增强。本研究发现了具有诱导神经细胞分化活性的高活性化合物，为开发防治AD等神经退行性疾病的药物奠定基础。此外对川楝素的结构进行了深入研究，是本项目的另一个突破。