title: Synthesis and in vitro antitumor evaluation of dihydroartemisinin-cinnamic acid ester derivatives.
abstract: To explore novel high efficiency and low toxicity antitumor agents, a series of dihydroartemisinin-cinnamic acid ester derivatives modified on C-12 and/or C-9 position (s) were synthesized and the in vitro antitumor activities against PC-3, SGC-7901, A549 and MDA-MB-435s cancer cell lines were assessed. The hybrids (3-36) were prepared by esterification of 9α-hydroxyl-dihydroartemisinin (9α-OH DHA), the biotransformation product of dihydroartemisinin (DHA), and cinnamic acid derivatives. Compound 17 (IC50 = 0.20 μM) was the most potent anti-proliferative agent against the human lung carcinoma A549 cells, although it displayed low cytotoxicity on normal hepatic L-02 cells. The mechanism of action of compound 17 was further investigated by analysis of cell apoptosis and intracellular ROS generation. The results indicated that both ROS and ferrous ion contributed to the compound 17-induced cell death. Meanwhile, high intracellular ferrous ion and endogenous oxidative stress in A549 cells made them easier to suffer to compound 17-induced apoptosis. Our promising findings indicated the compound 17 could stand as drug candidate against lung cancer for further investigation.
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, Jiangsu 211198, China.
authors.forename: Cang-Cang
authors.initials: CC
authors.lastname: Xu
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, Jiangsu 211198, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Deng
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, Jiangsu 211198, China.
authors.forename: Meng-Lin
authors.initials: ML
authors.lastname: Fan
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, Jiangsu 211198, China.
authors.forename: Wen-Bo
authors.initials: WB
authors.lastname: Lv
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, Jiangsu 211198, China. Electronic address: liujihua@cpu.edu.cn.
authors.forename: Ji-Hua
authors.initials: JH
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, Jiangsu 211198, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: boyangyu59@163.com.
authors.forename: Bo-Yang
authors.initials: BY
authors.lastname: Yu
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D037621:Artemisinins / Q000737:chemistry*; D045744:Cell Line, Tumor / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D002934:Cinnamates / Q000737:chemistry*; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006801:Humans; D007501:Iron / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D037621:Artemisinins; D002934:Cinnamates; D017382:Reactive Oxygen Species; C029010:cinnamic acid; C039060:artenimol; D007501:Iron
keywords: Antitumor; Apoptosis; Dihydroartemisinin-cinnamic acid ester derivatives; Ferrous ion; Oxidative stress; ROS