Dithiol‐Activated Bioorthogonal Chemistry for Endoplasmic Reticulum‐Targeted Synergistic Chemophototherapy

Abstract The controlled intracellular release of nitrite is still an unmet challenge due to the lack of bio‐friendly donors, and the antitumor effect of nitrite is limited by its physiologically inert activity. Herein, we designed benzothiadiazole‐based organic nitrite donors that are stable against bio‐relevant species but selectively respond to dithiol species through S N Ar/intramolecular cyclization tandem reactions in the aqueous media. The bioorthogonal system was established to target the endoplasmic reticulum (ER) of liver cancer HepG2 cells. The nitrite and nonivamide were coupled to induce elevation of intracellular levels of calcium ions as well as reactive oxygen/nitrogen species, which resulted in ER stress and mitochondrial dysfunction. We demonstrated that a combination of photoactivation and “click to release” strategy could enhance antitumor effect in cellular level and show good potential for cancer precision therapy.