抗肝癌干细胞化合物Ovatodiolide的构效关系研究和作用靶点探索

Recurrence and metastasis of hepatocellular carcinoma (HCC) is the most difficult problem in clinical treatment of HCC. Hepatocellular carcinoma stem cells play important roles in HCC relapse and metastasis. However, there are few compounds that can selectively target hepatocellular carcinoma stem cells. Previously, we discovered ovatodiolide could eliminate hepatocellular carcinoma stem cells. However, its anti-HCC activity is weak and the bioavailability is very low. Therefore, we plan to modify the structure of ovatodiolide by total synthesis and semi-synthesis to explore the structure-anti-hepatocellular carcinoma stem cell activity-metabolic stability relationships for addressing these drawbacks. It is expected to find 3-5 ovatodiolide analogues with high metabolic stability and selective targeting hepatocellular carcinoma stem cells. These analogues will be further evaluated for their efficacy on targeting hepatocellular carcinoma stem cell and in vivo anti-HCC activity. It is expected to find 1-2 active compounds which can selectively eliminate hepatocellular carcinoma stem cells and have significant pharmacodynamic effects in vivo. Furthermore, the probe of the most active compound was synthesized to explore the target of ovatodiolide. This project will provide guidance for the rational design and rapid discovery of active compounds against hepatocellular carcinoma stem cells, which will provide base for solving the recurrence and metastasis problems in clinical treatment of hepatocellular carcinoma.

肝癌的复发和转移是肝癌临床治疗中面临的最大难题，肝癌干细胞是肝癌复发、转移的根本原因，但能选择性靶向肝癌干细胞的化合物非常少。前期研究发现Ovatodiolide具有抗肝癌干细胞活性，但活性较弱、生物利用度低，限制了其进一步应用。本项目针对其存在的问题，拟通过全合成和半合成的手段，对Ovatodiolide进行系统的结构修饰，探索其结构-抗肝癌干细胞活性-代谢稳定性三重构效关系。期望发现3-5个选择性靶向肝癌干细胞、代谢稳定性高的Ovatodiolide类似物，进行体内靶向肝癌干细胞作用确认并进行体内药效评价，期望发现1–2个经体内外验证能选择性清除肝癌干细胞且体内药效显著的活性物质。最优化合物合成其活性分子探针，研究Ovatodiolide类化合物的作用靶点。为合理设计、快速发现抗肝癌干细胞活性化合物提供指导，为解决肝癌的复发和转移奠定坚实的物质基础。

肝癌的复发和转移是肝癌临床治疗中面临的最大难题，肝癌干细胞是肝癌复发、转移的根本原因。为解决Ovatodiolide在靶向肝癌干细胞中存在的活性弱和生物利用度低的问题而对其进行了系统的结构改造。通过体外检测修饰后化合物的抗肝癌活性，初步总结了Ovatodiolide结构与抗肝癌活性之间的构效关系，得到了抗肝癌活性提高50倍左右的衍生物；采用“双缓”策略对最优衍生物进行成药性改造并进一步进行了体内药效评价。靶点探索方面，合成了Ovatodiolide及最优衍生物的分子探针，利用点击化学反应确定了Ovatodiolide类化合物的作用靶点为MTA2蛋白，且共价结合的氨基酸位点为Cys209和Cys261。对Ovatodiolide调控MTDH的作用机制的研究表明Ovatodiolide通过下调SP1蛋白表达从而抑制MTDH基因转录进而调节JAK/STAT3信号通路靶向抑制肝癌干细胞。本研究为后续发现新型抗肝癌药物提供了重要支撑，为解决肝癌临床治疗面临的复发难题奠定了坚实的物质基础。同时Ovatodiolide作用靶点的发现和作用机制研究为后续合理设计、快速发现抗肝癌活性化合物提供指导。