Bioactivatable reductive cleavage of azobenzene for controlling functional dumbbell oligodeoxynucleotides

Bioactivatable reductive cleavage of azobenzene was applied in an “intelligent” system with oligodeoxynucleotides to control functional nucleic acids by GSH. [Display omitted] •mAzo was more effectively recognized and cleaved by glutathione.•mAzo is inserted to dumbbell asODNs and modulate their hybridization to nucleic acids.•AZ18O series could be applied to modulate the gene expression in cancer cells.•This finding would provide a valuable strategy for tunable cell release of ODNs. Application of stimuli-responsive bioactive molecules is an attractive strategy due to use for target special tissues and cells. Here, we reported synthesis of an azo-linker, 2,2′-dimethoxyl-4,4′-dihydroxymethylazobenzene (mAzo), which was more effectively recognized and cleaved by reducing glutathione (GSH) via comparing with 4,4′-dihydroxymethylazobenzene (Azo). In addition, mAzo is further exploited to engineer dumbbell asODNs, which could result in the release of asODNs and thus modulate their hybridization to target nucleic acids. The present study is the first example to disclose efficient reductive cleavage of azobenzene by GSH to generate aromatic amine. This would provide a valuable strategy for tunable cell-specific release of ODNs and modulation of known disease-causing gene expression in cancer cells.