Reactive Oxygen Species (ROS) Inducible DNA Cross-Linking Agents and Their Effect on Cancer Cells and Normal Lymphocytes

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• 作者：Wenbing Chen ; Kumudha Balakrishnan ; Yunyan Kuang ; Yanyan Han ; Min Fu ; Varsha Gandhi ; Xiaohua Peng
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：June 12, 2014
• 年：2014
• 卷：57
• 期：11
• 页码：4498-4510
• 全文大小：646K
• 年卷期：v.57,no.11(June 12, 2014)
• ISSN：1520-4804

文摘

Reducing host toxicity is one of the main challenges of cancer chemotherapy. Many tumor cells contain high levels of ROS that make them distinctively different from normal cells. We report a series of ROS-activated aromatic nitrogen mustards that selectively kill chronic lymphocytic leukemia (CLL) over normal lymphocytes. These agents showed powerful DNA cross-linking abilities when coupled with H<sub>2sub>O<sub>2sub>, one of the most common ROS in cancer cells, whereas little DNA cross-linking was detected without H<sub>2sub>O<sub>2sub>. Consistent with chemistry observation, in vitro cytotoxicity assay demonstrated that these agents induced 40鈥?0% apoptosis in primary leukemic lymphocytes isolated from CLL patients but less than 25% cell death to normal lymphocytes from healthy donors. The IC<sub>50sub> for the most potent compound (2) was 5 渭M in CLL cells, while the IC<sub>50sub> was not achieved in normal lymphocytes. Collectively, these data provide utility and selectivity of these agents that will inspire further and effective applications.