First total synthesis, antitumor evaluation and target identification of mornaphthoate E: A new tubulin inhibitor template acting on PI3K/Akt signaling pathway

Mornaphthoate E (MPE) is a prenylated naphthoic acid methyl ester isolated from the roots of a famous Chinese medicinal plant Morinda officinalis and show 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 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.