Novel agents derived from natural product β-elemene: A second round of design and synthesis to enhance antitumor properties

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry Pub Date : 2025-02-22 DOI:10.1016/j.bmc.2025.118129

Zhouyan Liu , Tong Li , Chenglei Gu , Cheng Chen , Ziwei Tang , Yanyan Feng , Chen Zhou , Jinyi Xu , Jichao Chen

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Abstract

Natural products play a key role in drug discovery and development. The natural sesquiterpene, β-elemene, has been approved as an antitumor drug in China. Despite showing few side effects, the moderate antitumor potency of β-elemene hampers its wide application in clinic. A second round of design and synthesis of β-elemene derivatives was carried out based on our previous prodrug-like ester derivatives. The resulting twenty-nine compounds (except 10c) exhibited enhanced antitumor activity compared with β-elemene and its ester derivative 3. The optimal compound 10a possessed low micromolar antiproliferative activities against three human cancer cell lines (SGC-7901, HeLa, and U87), more potent than positive control cisplatin. The mechanism studies indicate that compound 10a caused arrest of the cell cycle along with inhibition of microtubules, induced apoptosis via a ROS-involved mitochondrial apoptotic pathway, and dampened cell migration and invasion with changes of related protein (MMP-9 and p-FAK^Y397) expressions. Collectively, the promising antitumor efficacy of compound 10a would make it a potential lead compound in anticancer drug development.

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从天然产物β-榄香烯衍生的新型药物：第二轮设计和合成以增强抗肿瘤特性

天然产物在药物发现和开发中起着关键作用。天然倍半萜β-榄香烯已被中国批准为抗肿瘤药物。虽然β-榄香烯的副作用少，但其抗肿瘤能力较弱，阻碍了其在临床上的广泛应用。第二轮设计和合成β-榄香烯衍生物的基础上，我们的前药类酯衍生物。所得29种化合物（10c除外）与β-榄香烯及其酯衍生物3相比，表现出更强的抗肿瘤活性。最佳化合物10a对三种人类癌细胞系（SGC-7901， HeLa和U87）具有低微摩尔抗增殖活性，比阳性对照顺铂更有效。机制研究表明，化合物10a通过抑制微管导致细胞周期阻滞，通过ros参与的线粒体凋亡通路诱导细胞凋亡，通过改变相关蛋白（MMP-9和p-FAKY397）表达抑制细胞迁移和侵袭。综上所述，化合物10a具有良好的抗肿瘤作用，有望成为抗癌药物开发的先导化合物。

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来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.