研究表明，五环三萜类天然产物具有多种重要的生物活性。23-羟基白桦酸(23-HBA)是从中药白头翁中发现的五环三萜类化合物，对多种肿瘤具有较好的抑制作用。我们前期对23-HBA的半合成、结构修饰和生物活性开展了较为系统的研究，获得了初步构效关系和具有研究潜力的衍生物，利用荧光探针初步证明了该化合物主要定位在线粒体部位。本项目拟在此基础上深入研究，围绕成药性继续进行结构改造，通过全面生物活性评价，完善构效关系，为发现结构新颖的抗肿瘤候选新药奠定坚实的基础；同时，为探索23-HBA的作用靶标，选择C-23位羟基作为探针分子功能基团引入位点，构建生物素型、Bio-orthogonal和光亲和标记型等基于23-HBA的小分子探针化合物库；通过亲和色谱进行靶点垂钓以及电泳和质谱分析，开展靶标蛋白确定以及作用机理探索研究，为获得高效低毒、成药性优良的基于五环三萜类天然活性产物的创新药物提供理论依据。

Pentacyclic triterpenoids are the most common triterpenoids that have shown various bioactivities, such as anti-tumor, anti-bacterial, anti-inflammatory and metabolic regulatory activity. Betulinic acid (BA), is one of the most well-known and well-studied triterpenes. 23-Hydroxybetulinic acid (23-HBA) is a natural lupane-type pentacyclic triterpene, which can be considered as hydroxy alternative of BA and displays similar anti-tumor activities as BA. Based on our previous research findings, our current research work is intended to obtain new candidates of anti-tumor agent, so the structural modification and optimization of 23-HBA will be accomplished by employing a comprehensive drug design approach of tumor-targeting or prodrug. .Moreover, despite various anti-tumor activities, the mechanism of action of 23-HBA remains unknown and the validation of its target is highly desirable. This led us to the design of 23-HBA probes with a photoactive moiety or a biotin group at the C-23 position based on the SARs obtained by our group. The mechanism underlying the anticancer activity of these probes will be studied at the levels of molecule, cell, and tissue by techniques such as flow cytometry, Western blot and gene amplification. These studies will facilitate the mechanistic study of 23-HBA for its cellular localization and target validation..It is expected that this study will provide a promising approach to rapidly screen the new targets of natural triterpenoids and will contribute to the lead discovery and opitimization of pentacyclic triterpenes.