海南黄皮属植物中多靶点酪氨酸激酶抑制剂的发现及其作用机制研究

靶向抗肿瘤药物因其选择性强，毒副作用小是未来抗肿瘤药物的重点研究方向。目前已经上市的靶向小分子抗肿瘤药物主要为酪氨酸激酶抑制剂。这些药物目前大多为合成药物，尚未见天然小分子靶向抗肿瘤药物的上市。在我们前期研究中发现海南特有植物海南黄皮的总生物碱提取物具有显著的抗肿瘤活性，同时表现出了显著的多靶点酪氨酸激酶抑制活性，进而，在活性筛选结果的指导下对海南黄皮总生物碱提取物的化学成分进行了初步研究，发现了系列结构新颖、多靶点酪氨酸激酶抑制活性显著的生物碱类化合物，基于以上这些，本项目拟采用植物化学-生物学相结合的方法，对分布于海南的三种黄皮属植物中的生物碱类化学进行系统研究，建立相应化合物库，并对分离得到的化合物进行抗肿瘤活性评价和多靶点酪氨酸激酶抑制活性评价，寻找并发现具有显著生物活性的化合物，总结构效关系，选择性地开展活性化合物的作用机理研究，为发现高效、低毒的靶向抗肿瘤新药提供科学依据。

The discovery of targeted anti-cancer drugs will be the focus of anti-cancer drugs in future due to their selective killing of tumor cells and fewer side effects. Tyrosine kinase inhibitors accounted for most of the targeted small molecule anti-cancer drugs already on the market. Among these targeted anti-cancer drugs, most of them are currently synthetic drugs, until now, there is no natural small molecules had been listed as targeted anti-cancer drugs. In our previous study, we found that the anti-tumor activities of the total alkaloid extract of Clausena hainanensis, only distributed in Hainan island, were very significant in vitro, as well as exhibited remarkable multi-target tyrosine kinase inhibitory activities. Under the guidance of activity screening results, the chemical investigation of C. hainanensis had led to the isolation of a series of novel alkaloids with significant multi-target tyrosine kinase inhibitory activities. Based on these, this project aimed at the discovery of a variety of alkaloids from three Clausena species distributed in Hainan Island and the establishment of alkaloids library. The studies on their anti-tumor activities and multi-target tyrosine kinase inhibitory activities, structure-activity relationships, and anti-tumor mechanisms could provide scientific basis for the discovery of highly efficient and low toxic targeted anti-cancer drugs.