三种米仔兰属药用植物中抗多药耐药肿瘤活性成分的发现及作用机制研究

Multidrug resistance is the biggest obstacle in clinical tumor therapy. In preliminary work, several new triterpenoids and pregnan steriods were isolated from the stem of Aglaia abbreviata. Two of these new isolates showed significant cytotoxic activity against the multidrug resistant cells and sensitive ones. The targets mainly include the apoptosis pathway and drug resistant protein. In this project, we will firstly finish the bioassay-guided fractionation of extracts prepared from the plants with anti-multidrug resistant tumor activity. It will be in progress that in vitro and in vivo activity evaluation of the resulting constituents using cell, zebrafish and nude mice models. And the mechanism of the active compounds will be clarified by molecular biological methods. And we will screen the characteristic targets. After that, we can summarize the experimental experience to improve the isolation condition, and select the rational evaluation targets to establish the screening template with anti-drug-resistant tumor activity. Therefore, an efficient method for separating and screening natural products with familiar structure could be built. And, we will apply the method to find the constituents from Aglaia perviridis and Aglaia elliptifolia Merr.. It could verify the feasibility of the method and help to optimize it. Finally，we will evaluate these active constituents utilizing the methods of principal components analysis and molecular docking experiments toward targets, which will obtain structure-activity relationship and guide the discovery and structural modification of lead compounds. The results will elucidate the chemical composition of three kinds of Aglaia plants and find potential lead compounds. The active mechanism and structural basis will also be clarified. It may provide new ideas for relative researches on the active ingredients of herbal medicine, and benefit the research and development of traditional Chinese drug and natural drug.

多药耐药是临床肿瘤治疗的最大障碍。前期已从缩序米仔兰中分离出多个三萜和孕甾类新化合物，其中两个新化合物对多药耐药肿瘤有较强的抑制作用，主要靶点为凋亡通路和耐药蛋白。本课题将首先以活性机制为指导，继续完成其化学成分研究，并使用细胞、斑马鱼及裸鼠模型对活性组分进行体内外活性评价；同时借助分子生物学手段研究优势化合物的作用机制，以筛选特征性评价靶点，由此构建一种高效的、针对同类天然产物的提取分离、活性筛选方法。然后，运用所建方法，结合体内体外活性评价，从同属植物碧绿米仔兰和椭圆米仔兰中分离、筛选出活性化合物，验证并优化所建方法。最终，通过主成分分析法和靶点的分子对接实验来评价所得到的活性产物，获得构效规律，以进一步指导先导化合物的发现及结构改造。研究结果有助于阐明三种药用植物的化学成分、获取活性化合物并揭示其活性机制，为抗多药耐药肿瘤的新药研发提供先导化合物，为相关中药和天然药物研究提供新思路。

多药耐药是临床肿瘤治疗的最大障碍。本课题对米仔兰属药用植物中抗多药耐药活性成分进行研究，从椭圆叶米仔兰中分离出30个化合物，其中有9个新化合物，从碧绿米仔兰中分离得到27个化合物，其中有7个新化合物，并使用细胞、斑马鱼模型对活性组分进行体内外活性评价；由此构建一种高效的、针对同类天然产物的提取分离、活性筛选方法。研究结果有助于阐明三种药用植物的化学成分、获取活性化合物并揭示其活性机制，为抗多药耐药肿瘤的新药研发提供先导化合物，为相关中药和天然药物研究提供新思路。