Mornaphthoate E (MPE) is a prenylated naphthoic acid methyl ester isolated from the roots of a famous Chinese medicinal plant 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 anti-tumor activity of MPE was first assessed for both enantiomers in two breast cancer cells, with the levoisomer exerting slightly better potency. The anti-tumor effect was further verified by applying the racemate in an orthotopic autograft mouse model. Notably, MPE exerted promising anti-metastasis activity both and 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 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.

中文翻译：

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草萘酸E的首次全合成、抗肿瘤评价及靶点鉴定：作用于PI3K/Akt信号通路的新型微管蛋白抑制剂模板

Mornaphthoate E (MPE) 是一种从著名中药植物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，首先在两个乳腺癌细胞中评估了 MPE 的两种对映体的抗肿瘤活性，其中左旋异构体的效力稍好一些。通过将外消旋体应用于原位自体移植小鼠模型，进一步验证了其抗肿瘤作用。值得注意的是，MPE 在治疗剂量下对小鼠表现出有希望的抗转移活性，并且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，扰乱了调节 PI3K/Akt 信号传导的微管的动态平衡。总之，我们的工作为未来设计和开发下一代微管蛋白靶向化疗药物提供了新的化学模板。