title: Probing the Anticancer Action of Oridonin with Fluorescent Analogues: Visualizing Subcellular Localization to Mitochondria.
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.
authors.affiliation: State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University , 24 Tong Jia Xiang, Nanjing 210009, P. R. China.
authors.forename: Shengtao
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai 201203, P. R. China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University , 24 Tong Jia Xiang, Nanjing 210009, P. R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yao
authors.affiliation: State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University , 24 Tong Jia Xiang, Nanjing 210009, P. R. China.
authors.forename: Hao
authors.initials: H
authors.lastname: Cai
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University , Tianjin 300071, P. R. China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Miao
authors.affiliation: Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University , Shanghai 200240, P. R. China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wu
authors.affiliation: College of Pharmacy and Health Sciences, St. John's University , 8000 Utopia Parkway, Queens, New York, New York 11439, United States.
authors.forename: Dong-Hua
authors.initials: DH
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University , 24 Tong Jia Xiang, Nanjing 210009, P. R. China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University , 24 Tong Jia Xiang, Nanjing 210009, P. R. China.
authors.forename: Weijia
authors.initials: W
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University , 24 Tong Jia Xiang, Nanjing 210009, P. R. China.
authors.forename: Hequan
authors.initials: H
authors.lastname: Yao
authors.affiliation: College of Pharmacy and Health Sciences, St. John's University , 8000 Utopia Parkway, Queens, New York, New York 11439, United States.
authors.forename: Zhe-Sheng
authors.initials: ZS
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University , 24 Tong Jia Xiang, Nanjing 210009, P. R. China.
authors.forename: Jinyi
authors.initials: J
authors.lastname: Xu
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D045786:Diterpenes, Kaurane / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005456:Fluorescent Dyes / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D045786:Diterpenes, Kaurane; D005456:Fluorescent Dyes; C011959:oridonin