Xiaohua Peng

Three compounds with arylboronate esters conjugated with two equivalent nitrogen mustards [bis(2‐chloroethyl)methylamine, HN2] have been synthesized and characterized. These inactive small molecules selectively react with H 2 O 2 to produce multiple DNA cross‐linkers, such as two HN2 molecules alongside a bisquinone methide (bisQM), leading to efficient DNA ICL formation. In comparison to other amine functional groups, using HN2 as a leaving group greatly improves the DNA cross‐linking efficiency of these arylboronate esters as well as cellular activity. The introduction of HN2 in these arylboronate ester analogues favored the generation of bisQM that can directly cross‐link DNA. Two equivalents of HN2 are also generated from these compounds upon treatment with H 2 O 2 , which directly produces DNA ICL products. The cumulative effects of HN2 and bisQM on DNA cross‐linking makes these molecules highly effective H 2 O 2 ‐inducible DNA ICL agents. The three compounds with HN2 as a leaving group showed greatly enhanced cytotoxicity towards cancer cells in comparison to those containing trimethyl amine as a leaving group. This provides an effective strategy for further design of novel potential ROS‐activated anticancer prodrugs.