Pristimerin是一种天然三萜类化合物，因其多种生物活性而受到药物化学家的广泛关注。然而，pritimerin的结构修饰，特别是那些旨在发现抗肿瘤药物的修饰，相对有限。在本研究中，通过支架跳跃策略设计了两个系列的分别含有苯基恶唑和喹喔啉部分的pritimerin衍生物。合成目标化合物并使用 MTT 测定分析其体外细胞毒活性。最有效的细胞毒性化合物 (21o) 显着抑制 MCF-7 细胞的增殖，IC50 值为 2.0 μM，比 pritimerin (IC50 = 3.0 μM) 强 1.5 倍。与pritimerin相比，化合物21o对MCF-7和MCF-10A细胞系的选择性提高最大（25.7倍）。进行透射电子显微镜、单丹磺酰尸胺和 DCFH-DA 染色、蛋白质印迹和不同抑制剂测定来阐明化合物 21o 的作用机制。化合物 21o 通过激活 ROS/JNK 信号通路诱导 MCF-7 细胞中自噬介导的细胞死亡。因此，将喹喔啉亚结构整合到pritimerin中可能有利于增强其细胞毒活性。化合物 21o 可作为开发乳腺癌新疗法的先导化合物。

Pristimerin is a natural triterpenoid that has received much attention from medicinal chemists for its multiple biological activities. However, structural modifications of pristimerin, especially those aimed at discovering antitumor agents, are relatively limited. In this study, two series of pristimerin derivatives containing phenyloxazole and quinoxaline moieties, respectively, were designed via the scaffold hopping strategy. The target compounds were synthesized and analyzed for their cytotoxic activities in vitro using the MTT assay. The most potent cytotoxic compound (21o) significantly inhibited the proliferation of MCF-7 cells with an IC50 value of 2.0 μM, 1.5-fold more potent than pristimerin (IC50 = 3.0 μM). Compared with pristimerin, compound 21o displayed the greatest improvement in selectivity (25.7-fold) against the MCF-7 and MCF-10A cell lines. Transmission electron microscopy, monodansylcadaverine and DCFH-DA staining, Western blotting, and different inhibitor assays were performed to elucidate the mechanism of action of compound 21o. Compound 21o induced autophagy-mediated cell death in MCF-7 cells by activating the ROS/JNK signaling pathway. Therefore, incorporating a quinoxaline substructure into pristimerin could be advantageous for enhancing its cytotoxic activity. Compound 21o may serve as a lead compound for developing new therapies to treat breast cancer.