冬凌草甲素是近年来药物化学家密切关注的一种抗肿瘤对映贝壳杉烷二萜类化合物。在此，通过6步合成获得了一种新型的6,20-环氧A环修饰冬凌草甲素衍生物2。合成了一系列2的14-O衍生物（EpskA1-EpskA24）以进一步增强活性。基于对MCF-7、A549和L-02细胞的细胞毒性，选择EpskA9、EpskA10和EpskA21进行进一步筛选，以获得更广泛的抗肿瘤谱。总的来说，EpskA21 在 MCF-7 和 MIA-PaCa-2 细胞中表现出最有效的抗增殖活性，抑制增殖和迁移，并诱导细胞凋亡和细胞周期停滞。借助网络药理学分析，选择凋亡相关蛋白并通过蛋白质印迹法进一步检测。观察到 PI3K/AKT 的抑制以及 Bax/Bcl-2 比值、Cyt-C、cleaved-Caspase-9、cleaved-Caspase-3 和 cleaved-PARP 水平的增加，表明 EpskA21 通过线粒体诱导细胞凋亡途径。鉴于还观察到 DR5 表达增加和激活的 Caspase-8，外源性细胞凋亡途径也可能与抗肿瘤作用有关。版权所有 © 2024 Elsevier Inc. 保留所有权利。

Oridonin is an antitumor ent-kaurane diterpenoid that medicinal chemists have been paying close attention to in recent years. Herein, a novel 6,20-epoxy A-ring modified oridonin derivative 2 was obtained by a 6-step synthesis. A series of 14-O derivatives of 2 (EpskA1-EpskA24) were synthesized to further enhance the activity. Based on their cytotoxicity against MCF-7, A549 and L-02 cells, EpskA9, EpskA10 and EpskA21 were chosen for further screening to obtain a wider antitumor spectrum. Collectively, EpskA21 showed the most potent antiproliferative activity, inhibiting proliferation and migration, and inducing apoptosis and cell cycle arrest in MCF-7 and MIA-PaCa-2 cells. With the help of network pharmacology analysis, apoptosis-related proteins were selected and further tested by western blot assay. The inhibition of PI3K/AKT and an increase in the levels of Bax/Bcl-2 ratio, Cyt-C, cleaved-Caspase-9, cleaved-Caspase-3 and cleaved-PARP was observed, indicating that EpskA21 induced apoptosis through the mitochondrial pathway. Given that an increase in DR5 expression and activated Caspase-8 were also observed, the extrinsic apoptosis pathway might also be related to the antitumor effect.Copyright © 2024 Elsevier Inc. All rights reserved.