2. Academic Validation
  3. Probing the Anticancer Action of Oridonin with Fluorescent Analogues: Visualizing Subcellular Localization to Mitochondria

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

  • J Med Chem. 2016 May 26;59(10):5022-34. doi: 10.1021/acs.jmedchem.6b00408.
Shengtao Xu 1,  Shanshan Luo 2,  Hong Yao 1,  Hao Cai 1,  Xiaoming Miao 3,  Fang Wu 4,  Dong-Hua Yang 5,  Xiaoming Wu 1,  Weijia Xie 1,  Hequan Yao 1,  Zhe-Sheng Chen 5,  Jinyi Xu 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University , 24 Tong Jia Xiang, Nanjing 210009, P. R. China.
  • 2 Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai 201203, P. R. China.
  • 3 State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University , Tianjin 300071, P. R. China.
  • 4 Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University , Shanghai 200240, P. R. China.
  • 5 College of Pharmacy and Health Sciences, St. John's University , 8000 Utopia Parkway, Queens, New York, New York 11439, United States.
PMID: 27089099 DOI: 10.1021/acs.jmedchem.6b00408
Abstract

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.

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