Mornaphthoate E (MPE) 是从著名中药巴戟天根中分离出来的异戊二烯化萘甲酸甲酯，对多种人类肿瘤细胞系具有显着的细胞毒性。本项目通过七步实现了(±)-MPE的首次全合成，总收率为5.6%。然后，首先在两种乳腺癌细胞中评估 MPE 的两种对映体的体外抗肿瘤活性，其中左旋异构体的效力稍好一些。通过在原位自体移植小鼠模型中应用外消旋体，进一步验证了体内抗肿瘤作用。值得注意的是，MPE 在体外和体内均表现出有前景的抗转移活性，并且在治疗剂量下对小鼠没有表现出明显的毒性。机理研究表明，MPE 作为微管蛋白聚合稳定剂，通过调节 PI3K/Akt 信号传导扰乱微管的动态平衡。总之，我们的工作为下一代微管蛋白靶向化疗的未来设计和开发提供了新的化学模板。© 2024 作者。

Mornaphthoate E (MPE) is a prenylated naphthoic acid methyl ester isolated from the roots of a famous Chinese medicinal plant Morinda officinalis and shows remarkable cytotoxicity against several human tumor cell lines. In the current project, the first total synthesis of (±)-MPE was achieved in seven steps and 5.6% overall yield. Then the in vitro anti-tumor activity of MPE was first assessed for both enantiomers in two breast cancer cells, with the levoisomer exerting slightly better potency. The in vivo anti-tumor effect was further verified by applying the racemate in an orthotopic autograft mouse model. Notably, MPE exerted promising anti-metastasis activity both in vitro and in vivo and showed no obvious toxicity on mice at the therapeutic dosage. Mechanistic investigations demonstrated that MPE acted as a tubulin polymerization stabilizer and disturbed the dynamic equilibrium of microtubules via regulating PI3K/Akt signaling. In conclusion, our work has provided a new chemical template for the future design and development of next-generation tubulin-targeting chemotherapies.© 2024 The Authors.