吴茱萸碱是我国传统中药吴茱萸果实中分离得到的生物碱。本课题组前期通过Top1抑制剂虚拟筛选研究，发现并验证了其Top1的抑制活性，通过结构优化设计与合成研究，得到一批抗肿瘤活性更好的吴茱萸碱衍生物，证明它们具有Top1/Top2双重抑制作用，并意外发现一个吴茱萸碱骨架跃迁化合物Evo223对结肠癌具有非常高的体内外抗肿瘤活性（体外IC50为1nM，体内2mg/kg抑瘤率为50%），而且毒性很低，但却丧失了Top1/Top2抑制活性，初步预试验证明可能具有全新的抗肿瘤作用机制。为此，本课题拟对吴茱萸碱进行系统的骨架跃迁设计、合成与抗肿瘤活性的研究，并采用基于生物素探针的化学蛋白质组学技术，深入研究高活性抗肿瘤化合物的作用机制和作用新靶标，总结吴茱萸碱分子骨架跃迁对抗肿瘤活性和作用机制影响的规律，高效率地发现具有自主知识产权、作用机制全新的抗肿瘤活性先导化合物，为开发新型抗肿瘤药物奠定基础。

Evodiamine is a quinazolinocarboline alkaloid isolated from the fruits of traditional Chinese herb Evodiae fructus. Previously, we identified evodiamine as a potent Top1 inhibitor by structure-based virtual screening. Further lead optimization studies led to the discovery of highly potent antitumor evodiamine derivatives as Top1/Top2 dual inhibitors. Among them, the evodiamine derivative Evo223 that was derived from scaffold hopping showed excellent antitumor activity against colon cancer with low toxicity (In vitro: IC50 = 1nM; In vivo: Tumor inhibition% = 50%, i.p. 2 mg/Kg).Interestingly, Evo223 lost the inhibitory activity toward Top1/Top2 and preliminary mechanism studies indicated that Evo223 acted by novel mechanisms. Thus, the present research proposal aims to perform systematic scaffold hopping design, synthesis and antitumor activity evaluations of evodiamine derivatives. The antitumor mechanism and molecular target of the highly active derivatives will be investigated by biotin probe-based chemoproteomic analysis. The effects of scaffold hopping of evodiamine on the antitumor activity and mode of action will be clarified. Moreover, this research project will efficiently identify novel antitumor lead compounds with self-owned intellectual properties and provide basis for the development of novel antitumor agents.

吴茱萸碱是我国传统中药吴茱萸果实中分离得到的生物碱。本课题组前期通过Top1抑制剂虚拟筛选研究，发现并验证了其Top1的抑制活性，通过结构优化设计与合成研究，得到一批抗肿瘤活性更好的吴茱萸碱衍生物，证明它们具有Top1/Top2双重抑制作用。为此，本课题对吴茱萸碱进行系统的骨架跃迁设计、合成与抗肿瘤活性的研究，并采用基于生物素探针的化学蛋白质组学技术，深入研究高活性抗肿瘤化合物的作用机制和作用新靶标，总结吴茱萸碱分子骨架跃迁对抗肿瘤活性和作用机制影响的规律，高效率地发现具有自主知识产权、作用机制全新的抗肿瘤活性先导化合物。本课题设计并合成得到12类新骨架化合物共计100余个，系统阐明了构效关系；发现3-氯-10-羟基氧代吴茱萸碱等高活性衍生物显示了优秀的体内外抗肿瘤活性，目前正作为候选药物进行成药性评价。对高活性化合物开展了作用机制研究，首次发现吴茱萸碱骨架跃迁衍生物具有Top1/Top2/Tubulin三重抑制作用；在本项目资助下，共发表SCI论文7篇，其中影响因子5分以上1篇，申请国家发明专利4项，授权3项。