八角属剧毒植物果实抗肝癌毒性成分快速制备、作用机制及八角茴香质量标准提升研究

STAT3通路在肝癌产生、侵袭和转移中起关键作用，是研究肝癌药物新靶点。八角属果实中，八角茴香无毒，其他植物均有毒，莽草和野八角最为剧毒。前期发现莽草和野八角二氯甲烷提取物对肝癌细胞株和STAT3显强活性，从中初步分离9个倍半萜等成分，采用MTT初筛显示化合物亦具强活性。由此提出两个假说：莽草和野八角独有且八角茴香不含有的差异成分，多为毒性成分，是开发细胞毒抗癌药物潜在资源；毒性成分可作为八角茴香标准中不得检出成分以提升质控标准。本研究拟跟踪活性提取物快速制备更多化合物，阐明抗肝癌构效关系，发现关键药效团与STAT3蛋白作用程度，应用计算机辅助药物设计研究构效关系及其与靶蛋白作用，体内评价抗肝癌效果，从分子-细胞-动物水平上阐明其物质基础和作用机理，发现细胞毒先导化合物，为开发提供基础。同时评价毒性成分的毒性程度，确定最具代表性毒性成分，作为八角茴香质量标准禁止检出成分，提升其质控水平。

STAT3 pathway is a new target of anti hepatoma drugs. It plays a key role in the generation, invasion and metastasis of hepatoma. Among the Illicium plants, anise is nontoxic, but the fruits of other plants are toxic, especially Illicium lanceolatum and I. simonsii, which may be rich in toxic ingredients. In the early stage, we found that dichloromethane extracts from the fruits of two plants showed strong activities on hepatoma cell line and STAT3 target. Then, we preliminarily isolated 9 sesquiterpenes and other components from these extracts. MTT test showed that most of these compounds also had strong activities. For this reason, we put forward the hypothesis: the components of I. lanceolatum and I. simonsii are owned by themselves, but anise does not contain, most of them are toxic components, which are potential resources for the development of cytotoxic drugs; toxic components can be used as prohibited components in the quality standard of anise, so as to improve its quality control standard. In this study, we intend to rapidly prepare more compounds, clarify the structure-activity relationship of anti hepatoma, find the degree of interaction between key pharmacophores and STAT3 protein, study the structure-activity relationship by using computer-aided drug design, evaluate the anti hepatoma effect of these compounds in vivo by using animal model, clarify the material basis and mechanism of action of these compounds from the molecular cellular animal level, and find the leading compounds to provide the basis for development. At the same time, evaluate the toxicity of toxic components, determine the most representative toxic component, let it be the component that can not be detected, and improve the quality control standard of star anise.