The host toxicity is the major concern for anticancer chemotherapeutic agents. We exploit the distinctive feature of cancer cells to develop drugs that target tumors while cause less damage to surrounding healthy cells. Many tumor cells contain high levels of reactive oxygen species (ROS) which makes them distinctively different from normal cells. A series of H2O2-activated DNA cross-linking agents have been successfully synthesized. These agents show powerful DNA cross-linking abilities when coupling with H2O2 which is considered as one of the most common ROS in cancer cells, whereas DNA cross-linking was not detected without H2O2. Consistent with the chemistry observation, in vitro cytotoxicity assay in respective cell lines demonstrated that these reagents exhibited high toxicities in cell lines, such as SR (Leukemia), NCI-H460 (Non-Small Cell Lung Cancer), and MDA-MB-468 (breast cancer), which are under oxidative stress. In addition, these compounds showed selective toxicity towards chronic lymphocytic leukemia while normal lymphocytes from healthy donors were less affected. The cellular study with or without N-acetylcysteine (ROS quencher) showed that these agents function through ROS-dependent mechanisms. Collectively, these data provide the utility and selectivity of these agents which should inspire further and effective application.

ROS-activated DNA interstrand cross-linking agents: Design, synthesis, and biological investigation

248th National Meeting (2014)

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