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Reducing host toxicity is one ofthe main challenges of cancer chemotherapy. Many tumor cells containhigh levels of ROS that make them distinctively different from normalcells. We report a series of ROS-activated aromatic nitrogen mustardsthat selectively kill chronic lymphocytic leukemia (CLL) over normallymphocytes. These agents showed powerful DNA cross-linking abilitieswhen coupled with H2O2, one of the most commonROS in cancer cells, whereas little DNA cross-linking was detectedwithout H2O2. Consistent with chemistry observation,in vitro cytotoxicity assay demonstrated that these agents induced 40–80%apoptosis in primary leukemic lymphocytes isolated from CLL patientsbut less than 25% cell death to normal lymphocytes from healthy donors.The IC50for the most potent compound (2)was ∼5 μM in CLL cells, while the IC50wasnot achieved in normal lymphocytes. Collectively, these data provideutility and selectivity of these agents that will inspire furtherand effective applications. [ABSTRACT FROM AUTHOR]