title: Reactive oxygen species (ROS) inducible DNA cross-linking agents and their effect on cancer cells and normal lymphocytes.
abstract: 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 H2O2, one of the most common ROS in cancer cells, whereas little DNA cross-linking was detected without H2O2. Consistent with chemistry observation, in vitro cytotoxicity assay demonstrated that these agents induced 40-80% apoptosis in primary leukemic lymphocytes isolated from CLL patients but less than 25% cell death to normal lymphocytes from healthy donors. The IC50 for the most potent compound (2) was ~5 μM in CLL cells, while the IC50 was not achieved in normal lymphocytes. Collectively, these data provide utility and selectivity of these agents that will inspire further and effective applications.
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee , 3210 N. Cramer Street, Milwaukee, Wisconsin 53211, United States.
authors.forename: Wenbing
authors.initials: W
authors.lastname: Chen
authors.forename: Kumudha
authors.initials: K
authors.lastname: Balakrishnan
authors.forename: Yunyan
authors.initials: Y
authors.lastname: Kuang
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Han
authors.forename: Min
authors.initials: M
authors.lastname: Fu
authors.forename: Varsha
authors.initials: V
authors.lastname: Gandhi
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Peng
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis; D001897:Boronic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D003432:Cross-Linking Reagents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D004952:Esters; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000473:pathology; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects*; D009588:Nitrogen Mustard Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D003432:Cross-Linking Reagents; D004952:Esters; D009588:Nitrogen Mustard Compounds; D011355:Prodrugs; D017382:Reactive Oxygen Species; D004247:DNA; D006861:Hydrogen Peroxide