Probing the Anticancer Action of Oridonin with Fluorescent Analogues: Visualizing Subcellular Localization to Mitochondria

详细信息    查看全文

• 作者：Shengtao Xu ; Shanshan Luo ; Hong Yao ; Hao Cai ; Xiaoming Miao ; Fang Wu ; Dong-Hua Yang ; Xiaoming Wu ; Weijia Xie ; Hequan Yao ; Zhe-Sheng Chen ; Jinyi Xu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：May 26, 2016
• 年：2016
• 卷：59
• 期：10
• 页码：5022-5034
• 全文大小：760K
• 年卷期：0
• ISSN：1520-4804

文摘

Oridonin (1) is a complex ent-kaurane diterpenoid exhibiting remarkable antitumor activity. However, the detailed mechanism or cellular target that underlies this activity has not yet been identified. Herein, we report an efficient approach for exploring the anticancer mechanism of oridonin through development of the potent fluorescent analogues. A series of novel fluorescent oridonin probes linked with coumarin moieties were designed, synthesized, and characterized. Fluorescence microscopy and confocal imaging studies suggested that fluorescent oridonin probe 17d was rapidly taken up into tumor cells and the mitochondrion was the main site of its accumulation. Moreover, we confirmed that cytochrome c played an important role in oridonin induced mitochondrion-mediated apoptosis and α,β-unsaturated ketone is the active moiety of oridonin, which is crucial to its uptake, localization, and cytotoxicity. Our results provide new insights on the molecular mechanism of oridonin and would be useful for its further development into an antitumor agent.