两种土家族药用植物靶向STAT3通路抗肿瘤活性成分及作用机制研究

STAT3 pathway plays a critical role in the development and progression of tumor, which makes that targeting the STAT3 pathway a promising way to treat cancer. Traditional folk medicinal plants are often used with a long history with definite therapeutic effect while less studied, thus they can be an important source for the discovery of new lead compounds. In our previous study of activity screening of 25 Tujia medicinal plants, we found that the extracts of Tinospora sagittata（Oliv.）Gagnep and Stephania herbacea Gagnep. could inhibit tumor cell proliferation and down regulate the phosphorylation of STAT3. We found four Clerodane-type diterpenoids from the extract of Tinospora sagittata（Oliv.）Gagnep, one of which showed definite anti-tumor activity. It indicate that it is possible to find new anti-tumor compounds from the two medicinal plants. This project aims at obtaining chemical constituents of the two medicinal plants under the guidance of activity and LC-MS/MS, finding active compouds through screening of anti-tumor activity and regulating STAT3 activity, evaluating the anti-tumor activity of the active compounds with in vitro and in vivo models, clarifying the mechanism of action of the active compounds regulating STAT3 pathway, thus to find new effective anti-tumor leading compounds and provide research basis for the development of the two Tujia medicinal plants.

STAT3通路在肿瘤发生发展过程中起到关键作用，使得靶向STAT3通路成为一种潜在的肿瘤治疗策略。我国民族药用植物应用历史悠久、疗效确切而系统研究较少，是新型先导化合物发现的重要资源。通过前期对25种来自土家族的药用植物的初步活性筛选，我们发现两种土家族药用植物青牛胆、铜锣七的提取物具有抑制肿瘤细胞增殖和抑制STAT3磷酸化水平的活性；对青牛胆的初步分离得到四个新型克罗烷型二萜化合物，其中一种具有抑制肿瘤细胞增殖的活性，表明从两种药用植物中得到抗肿瘤活性化合物具有可行性。本项目拟在活性跟踪及LC-MS/MS指导下对两种药用植物的化学成分进行分离与鉴定，通过抗肿瘤细胞增殖活性及调节STAT3活性筛选得到活性化合物，再通过体内外实验模型系统评价其抗肿瘤活性，研究活性化合物对STAT3通路的调节作用明确其作用机制，以期发现机制明确的新型抗肿瘤先导化合物，为两种土家族药用植物的开发提供研究基础。

特色民族药用植物是活性天然产物发现的重要资源。从民族药物中发现活性化合物对民族药物开发也有重要意义。本项目对两种土家族药用植物青牛胆和铜锣七的化学成分进行了系统的分离，并通过NMR、MS、X-ray单晶衍射等技术确定了其结构。从青牛胆中得到19个克罗烷型二萜类化合物，其中7个为新化合物；从铜锣七中得到6个生物碱类化合物，其中2个为新化合物。对单体化合物进行了抗肿瘤活性筛选，部分化合物显示一定的抑制肿瘤细胞增殖活性，并有潜在的STAT3抑制活性。本项目拓展了两种药用植物的化学成分及活性研究，为两种特色民族药物的开发提供了研究基础。