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

作　　者：Peipei Shan Tao Ye Ying-De Tang Hui Song Chao Wang Kongkai Zhu Feifei Yang Shi-Lei Zhang Pei-Wen Su Shuanhu Gao Hua Zhang 

机构地区：[1]Institute of Translational Medicine,the Affiliated Hospital of Qingdao University,College of Medicine,Qingdao University,Qingdao 266021,China [2]School of Biological Science and Technology,University of Jinan,Jinan 250022,China [3]Advanced Medical Research Institute,Cheeloo College of Medicine,Shandong University,Jinan 250012,China [4]College of Pharmaceutical Sciences,Soochow University,Suzhou 215127,China [5]School of Chemistry and Molecular Engineering,East China Normal University,Shanghai 200062,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第5期2177-2193,共17页药学学报（英文版）

基　　金：This project was financially supported by the National Natural Science Foundation of China(No.82073729,22225105).

摘　　要：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.

关 键 词：Mornaphthoate E Tubulin inhibitor ANTITUMOR ANTI-METASTASIS Breast cancer PI3K/AKT 

分 类 号：R587.1[医药卫生—内分泌]