State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
Bioorg Chem. 2021 Oct;115:105249. doi: 10.1016/j.bioorg.2021.105249. Epub 2021 Aug 8.
A large number of derivatives of natural pentacyclic triterpenoid oleanolic acid (OA) with various activities have been reported, including CDDO derivatives (CDDOs). CDDOs show potent antitumor activity, but they lack selectivity for tumor cells which causes serious side effects. In this study, based on the truth that tumor cells display higher mitochondrial membrane potential, to improve their mitochondrial-targeting ability, triphenylphosphine cations (TPP) or tricyclohexylphosphine cations (TCP) were linked to CDDO. Among these compounds, the TPP derivative 5b exhibited greater activity against the tumor cells than CDDO-Me, and the selectivity for the tumor cells was obviously improved. Further investigation revealed that the uptake of 5b in the mitochondria of MCF-7 cells was increased compared to CDDO-Me. In addition, 5b was able to cause mitochondrial membrane potential decline and cell cycle arrest. Furthermore, 5b caused apoptosis mainly through the mitochondria-mediated intrinsic pathway. Taken together, our study provides a possible solution to the poor selectivity of CDDOs, and regains confidence in the treatment of tumor with CDDOs.
已经报道了大量具有各种活性的天然五环三萜齐墩果酸（OA）的衍生物，包括 CDDO 衍生物（CDDOs）。CDDOs 表现出很强的抗肿瘤活性，但它们对肿瘤细胞缺乏选择性，这会导致严重的副作用。在这项研究中，基于肿瘤细胞显示更高的线粒体膜电位的事实，为了提高它们的线粒体靶向能力，三苯基膦阳离子（TPP）或三环己基膦阳离子（TCP）被连接到 CDDO 上。在这些化合物中，TPP 衍生物 5b 对肿瘤细胞的活性比 CDDO-Me 更强，对肿瘤细胞的选择性明显提高。进一步的研究表明，与 CDDO-Me 相比，5b 在 MCF-7 细胞的线粒体中的摄取增加。此外，5b 能够导致线粒体膜电位下降和细胞周期停滞。此外，5b 主要通过线粒体介导的内在途径引起细胞凋亡。总之，我们的研究为 CDDOs 的选择性差提供了一个可能的解决方案，并重新获得了用 CDDOs 治疗肿瘤的信心。
