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

Abstract

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. H 2 O 2 -inducible DNA ICL agents are highly selective for targeting cancer cells, as the concentration of H 2 O 2 is higher in cancer cells than normal cells. Previous studies have focused on arylboronate-based precursors, reacting with H 2 O 2 to generate reactive quinone methides (QMs) crosslinking DNA. Here we explore phenyl selenide-based precursors 1-3 as H 2 O 2 -inducible DNA ICL agents. The precursors 1-3 can be activated by H 2 O 2 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 paraposition 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 H 2 O 2 -inducible DNA interstrand cross-linkers.

New-generation advanced PROTACs as potential therapeutic agents in cancer therapy

“…B Chemical structures of the ROS-responsive PROTAC prodrug (adapted from [105]). C Chemical structures of the ROS-responsive PROTAC prodrugs (adapted from [106]) personalized medicine approaches for improved patient outcomes in oncology treatments.…”

Hydrogen Peroxide‐Inducible PROTACs for Targeted Protein Degradation in Cancer Cells

“…[27] Peng and our groups developed H 2 O 2 -responsive DNA interstrand crosslinking (ICL) agents with targeted anticancer activities utilizing aryboronates, boronic acids, or phenyl selenide as trigger units. [28][29][30][31][32][33] Recently, NAD(P)H quinone dehydrogenase 1 (NQO1) and ROS responsive PROTACs were reported to selectively suppress cancer cells growth by degrading BRD4 with cell-selectivity. [34,35]…”

Dual-responsive probe and DNA interstrand crosslink precursor target the unique redox status of cancer cells

“…14–16 Methods to improve selectivity employ a stimuli-inducible strategy, such as photoinduction, fluoride/NaIO 4 induction, H 2 O 2 induction, etc. 17–23 H 2 O 2 -inducible precursors are promising candidates as they can be activated by endogenous H 2 O 2 in cancer cells. However, some normal cells including macrophages, neutrophils and inflammatory cells, also contain high levels of H 2 O 2 , thereby causing possible interference.…”

“…18 Here, dual responsive precursor 14 was obtained by incorporation of a GSH-responsive trigger unit 2,4-dinitrobenzenesulfonamides (DNs) to our previously developed 13 with promising DNA crosslink ability. 23 We assessed its reactivity and selectivity via a DNA interstrand cross-link assay utilizing a 49-mer DNA duplex 15 . The strand 15a was FAM-labelled to facilitate fluorescence analysis.…”

“…The probe consists of three basic units: a GSH-responsive 2,4-dinitrobenzenesulfonamide (DNs) caged coumarin donor, an H 2 O 2 -inducible boronate-caged fluorescein acceptor, and a rigid piperazine linker. 25,26 To construct the probe, the carboxylic acid substituted fluorescein was first prepared from trimellitic anhydride and resorcinol as a mixture of 5 (6)carboxylic acid fluorescein. The pure 2 was obtained by baseinduced decomposition and recrystallization.…”