Oleanolic acid and its derivatives have been widely reported for their antitumor activities. Recently, the introduction of a triphenylphosphonium cation moiety has been described to improve the selectivity and cytotoxicity of pentacyclic triterpenoids by targeting the mitochondria of human cancer cells. In this work, a series of novel mitochondria-targeting oleanolic acid derivatives were synthesized and their antitumor activities assessed. The majority of the compounds are more cytotoxicity to cancer cells than normal cells, especially for 6c with IC₅₀ of 0.81 μM in A549 cells, which showed a slight increase compared to doxorubicin (0.97 μM). Mechanism studies demonstrated that 6c induced apoptosis of A549 cells in a dose-dependent manner, and reactive oxygen species production, mitochondrial membrane potential depolarization, and particularly pro-apoptotic proteins upregulated by western blotting experiment may be responsible for the results. Moreover, 6c arrested the cell cycle at G2/M phase and cell migration in A549 cells. Compound 6c had a comparable or somewhat improved activity to the positive control LY294002 in molecular docking studies and in vitro testing, demonstrating that the apoptosis mechanism may involve inhibition of the PI3K-Akt pathway. These results augur well for the use of 6c as a novel triphenylphosphonium-conjugated anticancer agent.

齐墩果酸及其衍生物的抗肿瘤活性已被广泛报道。最近，已经描述了引入三苯基鏻阳离子部分以通过靶向人类癌细胞的线粒体来提高五环三萜类化合物的选择性和细胞毒性。在这项工作中，合成了一系列新型线粒体靶向齐墩果酸衍生物，并评估了它们的抗肿瘤活性。大多数化合物对癌细胞的细胞毒性高于正常细胞，特别是对于6c ，在 A549 细胞中的 IC ₅₀为 0.81 μM，与多柔比星 (0.97 μM) 相比略有增加。机制研究表明，6c以剂量依赖性方式诱导 A549 细胞凋亡，活性氧的产生、线粒体膜电位去极化，特别是蛋白质印迹实验上调的促凋亡蛋白可能是导致结果的原因。此外，6c阻止了 G2/M 期的细胞周期和 A549 细胞中的细胞迁移。在分子对接研究和体外测试中，化合物6c的活性与阳性对照 LY294002 相当或有所改善，表明细胞凋亡机制可能涉及抑制 PI3K-Akt 途径。这些结果预示着6c作为一种新型三苯基鏻共轭抗癌剂的应用。