Phenyl Selenide‐Based Precursors as Hydrogen Peroxide Inducible DNA Interstrand Cross‐Linkers

DNA interstrand crosslinks (ICLs) are highly toxic DNA lesions, and induce cell death by blocking DNA strand separation. Most ICL agents aiming to kill cancer cells, also generate adverse side effects to normal cells. H2O2‐inducible DNA ICL agents are highly selective for targeting cancer cells, as the concentration of H2O2 is higher in cancer cells than normal cells. Previous studies have focused on arylboronate‐based precursors, reacting with H2O2 to generate reactive quinone methides (QMs) crosslinking DNA. Here we explore phenyl selenide‐based precursors 1–3 as H2O2‐inducible DNA ICL agents. The precursors 1–3 can be activated by H2O2 to generate the good benzylic leaving group and promote production of reactive QMs to crosslink DNA. Moreover, the DNA cross‐linking ability is enhanced by the introduction of substituents in the para‐position of the phenolic hydroxyl group. From the substituents explored (H, OMe, F), the introduction of electron donating group (OMe) shows a pronounced elevating effect. Further mechanistic studies at the molecular and DNA levels confirm alkylation sites located mainly at dAs, dCs and dGs in DNA. Additionally, cellular experiments reveal that agents 1–3 exhibit higher cytotoxicity toward H1299 human lung cancer cells compared to clinically used drugs, by inducing cellular DNA damage, apoptosis and G0/G1 cell cycle arrest. This study provides a strategy to develop H2O2‐inducible DNA interstrand cross‐linkers. Method to produce quinone methides (QMs): Phenolic hydroxyl group and benzylic leaving group are essential for the formation of QMs. In contrast to previous work on H2O2‐inducible formation of phenolic hydroxyl group to produce QMs, we show that H2O2‐inducible formation of a good benzylic leaving group, benzeneselenenic acid converted from phenyl selenoxide, evokes generation of QMs to crosslink DNA.