H O -Inducible DNA Cross-linking Agents Capable of Releasing Multiple DNA Alkylators as Anticancer Prodrugs.

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 O 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 O , which directly produces DNA ICL products. The cumulative effects of HN2 and bisQM on DNA cross-linking makes these molecules highly effective H O -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.