Radiation-Induced Clip Reaction of Sulfilimine in Living Cells

Abstract

Clip reactions featuring highly selective and efficient bond cleavage are powerful synthetic tools. Herein, a radiation-induced clip reaction of sulfilimine is established. Sulfilimines are quantitatively decomposed to phenothiazines and amines by radiation with a record-high radiolytic yield of 270.9 nM/Gy. This high efficiency and selectivity are attributed to the near-unity utilization of hydrated electrons and hydroxyl radicals, the two primary radiation-generated reactive species. The sulfilimine bond undergoes reductive cleavage by hydrated electrons to generate a phenothiazine radical cation and an amine. Then, phenothiazine radical cation is reduced to phenothiazine by hydroxyl radicals and water. The clip reaction exhibits a broad substrate scope, rapid reaction kinetics, and robust performance under typical interferences, particularly under biological conditions. By pairing with sulfilimine-based click reactions, it enables the radiation-triggered activation of bioactive molecules in living systems. Notably, the cytotoxicity of the sulfilimine-caged monomethyl auristatin E (MMAE) is dramatically reduced to be about 1/800 of MMAE. Upon 1 Gy γ-irradiation in cancer cells, the anticancer bioactivity can be restored. Moreover, the sulfilimine-caged MMAE shows a remarkable in vivo anticancer effect with γ-ray irradiation. This work establishes a new modality of bioorthogonal chemistry, expanding the chemical toolkit for spatiotemporally controllable bond cleavage in living systems. It also provides a molecular framework for radiotherapy-enhanced, spatiotemporally targeted chemotherapy.