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

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

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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.

Mornaphthoate ETubulin inhibitorAntitumorAnti-metastasisBreast cancerPI3K/Akt

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

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Institute of Translational Medicine,the Affiliated Hospital of Qingdao University,College of Medicine,Qingdao University,Qingdao 266021,China

School of Biological Science and Technology,University of Jinan,Jinan 250022,China

Advanced Medical Research Institute,Cheeloo College of Medicine,Shandong University,Jinan 250012,China

College of Pharmaceutical Sciences,Soochow University,Suzhou 215127,China

School of Chemistry and Molecular Engineering,East China Normal University,Shanghai 200062,China

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国家自然科学基金国家自然科学基金

8207372922225105

2024

10.1016/j.apsb.2024.02.012

药学学报(英文版)

药学学报(英文版)

CSTPCD
ISSN：
年,卷(期)：2024.14(5)
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