Abstract

Arylboronic acid/esters and phenyl selenides-based quinone methide (QM) precursors were reported to induce DNA interstrand crosslink (ICL) formation upon reaction with the inherently high concentrations of H 2 O 2 in cancer cells. However, some normal cells (such as macrophages) also contain high-levels of H 2 O 2 , which may interfere with precursors’ selectivity. In order to enhance the spatiotemporal specificity by the photolysis, we developed photo- and H 2 O 2 – dual-responsive DNA ICL precursors 1 – 3 , bearing a photo-responsive coumarin moiety and a H 2 O 2 inducible phenyl selenide group. Precursors 1 – 3 are efficiently activated by photoirradiation and H 2 O 2 to generate reactive QMs crosslinking DNA. Moreover, the reactivity of precursors can be modulated by the introduction of aromatic substituents (OMe, F), and the electron donating group (OMe) displays a more pronounced promoting effect on DNA ICL formation. A subsequent piperidine heat stability study confirmed that the formed QMs primarily alkylate dAs, dGs and dCs in DNA. Furthermore, 1 – 3 inhibit lung cancer cell (H1299) growth by inducing DNA damage and producing toxic reactive oxygen species (ROS) upon photolysis of released coumarin. This study illustrates the potent cytotoxicity achieved by novel photo/H 2 O 2 dual-responsive QM precursors 1 – 3 , affording a novel strategy for the development of inducible DNA interstrand cross-linkers.