小分子偶联药物是抗肿瘤药物研究新领域，通过偶联技术降低细胞毒类抗肿瘤药物毒性。课题组采用含氟药物合理设计新方法创新性提出喜树碱不稳定内酯环含氟生物电子等排体α-氟醚结构，优化获得高稳定性、高活性氟代喜树碱衍生物8l。本课题拟拓展α-氟醚结构至高喜树碱化合物，筛选高活性氟代高喜树碱衍生物。以能与氟代喜树碱起协同抗肿瘤效应的MDM2蛋白抑制剂PMI为小分子偶联化合物靶头，基于高活性氟代喜树碱8l和氟代高喜树碱化合物，通过选择性在肿瘤细胞代谢释放药物的链接基团连接靶头和活性化合物，设计新型氟代喜树碱小分子偶联化合物。通过稳定性、体外药物代谢、动物模型组织分布、体内外活性等研究化合物靶向作用和抗肿瘤活性，从中筛选氟代喜树碱小分子偶联候选药物。通过我们的合理设计和生物活性研究，为小分子偶联药物研究探索一条药物设计新思路。

Small molecule-drug conjugates(SMDCs) have become a novel opportunity for the development of selective cytotoxic agents. Based on the fluorinated drug design strategy, we firstly reported a new bioisostere α-fluorine ether and identified fluorinated camptothecin analogues (FCPT) with more stable lactone than natural camptothecin. Further optimization led to the discovery of potent antitumor FCPT analogue 8l. Thus, the present proposal aims to perform bioisostere expansion and find potent fluorinated homocamptothecin analogues. Moreover, the novel small molecule-drug conjugates based on 8l or potent fluorinated homocamptotheins and MDM2 inhibitor PMI will be designed. These compounds will be investigated by the stability, drug metabolism, tissue distribution and antitumor activity assays. This project will identify antitumor candidates of SMDCs based on fluorinated analogues and provide an new strategy for SMDCs design.