Hybrid Molecule from O2-(2,4-Dinitrophenyl)diazeniumdiolate and Oleanolic Acid: A Glutathione S-Transferase 蟺-Activated Nitric Oxide Prodrug with Selective Anti-Human Hepatoce
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- 作者：Junjie Fu ; Ling Liu ; Zhangjian Huang ; Yisheng Lai ; Hui Ji ; Sixun Peng ; Jide Tian ; Yihua Zhang
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：June 13, 2013
- 年：2013
- 卷：56
- 期：11
- 页码：4641-4655
- 全文大小：876K
- 年卷期：v.56,no.11(June 13, 2013)
- ISSN：1520-4804
文摘
A series of hybrids from O2-(2,4-dinitrophenyl)diazeniumdiolate and oleanolic acid (OA) were designed, synthesized, and biologically evaluated as novel nitric oxide (NO)-releasing prodrugs that could be activated by glutathione S-transferase 蟺 (GST蟺) overexpressed in a number of cancer cells. It was discovered that the most active compound, 21, released high levels of NO selectively in HCC cells but not in the normal cells and exhibited potent antiproliferative activity in vitro as well as remarkable tumor-retarding effects in vivo. Compared with the reported GST蟺-activated prodrugs JS-K and PABA/NO, 21 exhibited remarkably improved stability in the absence of GST蟺. Importantly, the decomposition of 21 occurred in the presence of GST蟺 and was much more effective than in glutathione S-transferase 伪. Additionally, 21 induced apoptosis in HepG2 cells by arresting the cell cycle at the G2/M phase, activating both the mitochondrion-mediated pathway and the MAPK pathway and enhancing the intracellular production of ROS.