活性天然产物在抗肿瘤新药研发中占有极其重要的地位，但其复杂结构导致的成药性差和作用靶点不明确一直是天然产物创新药物研发的主要障碍。冬凌草甲素是从香茶菜属植物中分离得到的贝壳杉烷型四环二萜活性天然产物，对多种肿瘤细胞具有广泛的抗肿瘤活性。为了探索其作用靶点，改善其成药性，申请人前期构建了冬凌草甲素四环二萜化合物库，探索了该类化合物的构效关系，获得了值得进一步优化的衍生物；并利用荧光探针研究了其抗肿瘤作用模式与机制。在此基础上，本项目拟根据前期研究结果，针对提高冬凌草甲素衍生物的抗肿瘤活性，平衡其LogP，改善水溶性及代谢稳定性四个方面进行新一轮的结构改造与优化，并进一步考察其成药性特征。同时拟利用生物正交策略，设计合成冬凌草甲素生物素探针分子，对其展开靶点垂钓与靶点验证研究，以探明冬凌草甲素的抗肿瘤作用靶点。为寻找和发现作用靶点明确，抗肿瘤活性强，成药性优良的抗肿瘤候选药物分子奠定基础。

Natural products (NPs) are vital in the discovery of novel antitumor drugs, however, the developments of NP-based antitumor drugs are hampered by their unidentified targets and structural complexity. Oridonin was an ent-kaurene diterpenoid isolated from genus Isodon (Rabdosia), and had extensive antiproliferative activities against many kinds of cancer cells. But its poor druggability and unidentified drug target greatly impeded its development and application for the preclinical use. In our previous work, we explored the structure-activity relationships of oridonin, and studied its mode of anticancer action by using fluorescent probes. Based on the above results, the present study will focus on the structural modification by strategies of activity improvement, LogP balance, metabolism and solubility improvements. Then, the druggabilities of target compounds will be evaluated including antiproliferative activities, metabolic stability and toxicity. On the other hand, oridonin-biotined probe will be synthesized based on the bioorthogonal strategy and used for the target fishing and identification. Our study will pave the way for the development of potent antitumor drugs with identified target and good druggability.