黄皮属植物中抗肿瘤活性分子的发现、构效关系及其机理研究

Cancer has high incidence and mortality, which do great harm to people’s life. To search efficient natural lead compound with low toxicity is one of the important direction in antitumor drug development. Coumarins and carbazole alkaloids are two kinds of compounds with the characteristic of small molecular weight, rich in type, simple structure and easy to modify, anti-tumor activity and so on. So they are good lead compounds. These two kinds of compounds mainly exists in the Rutaceae Clausena plants. Previously, we obtained many of these two kinds of compounds from stems, leaves and roots of Clausena excavata. Partial compounds showed their cytotoxity and antibacterial activity significantly, and the results exhibited a structure-activity relationship (SAR) to some extent. In order systematically and deeply to research the antitumor activity, SAR and mechanismof these substances, this project will carry out the directional isolation of novel coumarins and carbazole alkaloids from the stems, leaves and roots of Clausena vestita, Clausena anisum-olens, and Clausena lenis, on the basis of preliminary results. On the other hand, we will perform the structure transformation or modification by introducing active group to get many more candidate compounds, and search stronger active molecules by antitumor activity screening assay, to complete the SAR research and choose the more active molecules to explore the mechanism of coumarins and carbazole alkaloids. The implementation of project will promote the study of these two kinds of compounds, and lay a scientific foundation for finding efficient anticancer drug candidates or lead compounds.

癌症具有高发、高死亡率，对生命危害巨大，寻找高效低毒的天然抗肿瘤活性先导化合物是药物研发的重要方向之一。香豆素和咔唑生物碱是两类具有分子量小、类型丰富、结构简单易于修饰、抗肿瘤活性明显等特点，是优良的先导化合物。这两类成分在芸香科黄皮属植物中分布极为广泛。前期我们从黄皮属植物小叶臭黄皮中分离得到多种香豆素和咔唑生物碱，通过肿瘤细胞毒活性和抗菌活性筛选，发现部分化合物具有显著的活性，初步显示出一定的构效关系。本项目拟在已有研究基础上，从毛叶黄皮、细叶黄皮、光滑黄皮3种黄皮属植物的枝叶和根中定向系统发掘香豆素和咔唑生物碱成分，并通过结构修饰引入活性基团，进行抗肿瘤活性筛选，寻找更强活性分子，系统研究和完善其构效关系，并选择活性较好的分子初步探索其作用机制。项目的实施将会促进该两类化学成分的研究，为发现高效抗肿瘤候选药物或先导化合物奠定科学基础。

癌症具有高发、高死亡率，对生命危害巨大，寻找高效低毒的天然抗肿瘤活性先导化合物是药物研发的重要方向之一。基于此，本项目完成了4种黄皮属植物的枝叶部位化学成分的研究，获得了各种类型的化学成分147个，其中包括：生物碱64个、香豆素60个、倍半萜及其糖苷17个，其他类型化合物6个。通过三种肿瘤细胞株（肺癌 A549、胃癌 BGC-823、宫颈癌HeLa）细胞毒筛选，发现多数咔唑生物碱都对以上三种肿瘤细胞株均具有不同程度的细胞毒活性。通过对稻田稗草的生长抑制作用的研究，发现黄皮粗提物及部分化合物具有潜在的除草活性。通过对供试部分化合物的结构与效果的初步分析，发现咔唑生物碱的1位和3位负电性越强，2、4 和5位取代基的正电性越强越有利于提高其活性；2位和3位取代基体积增大不利于其活性提高。8位取代比5位取代的呋喃香豆素对稗草根的生长具有更强的抑制作用。氮上有甲基取代的黄皮酰胺对稗草根及幼芽的生长具有更强的抑制作用。