Design, Synthesis, and Evaluation of Diazeniumdiolate-Based DNA Cross-Linking Agents Activatable by Glutathione S-Transferase

A novel class of O2-(2,4-dinitrophenyl)-1-[N,N-bis(2-substituted ethyl)amino]diazen-1-ium-1,2-diolates 4–6 were designed, synthesized, and biologically evaluated. The most active compound 6 caused significant DNA damage by releasing N,N-bis(2-TsO ethyl)amine and two molecules of nitric oxide (NO) after activation by GST/GSH in cancer cells, being more cytotoxic against three cancer cell lines than a well-known diazeniumdiolate-based anticancer agent JS-K, suggesting that the strategy has potential to extend to other O2-derived diazeniumdiolates to improve anticancer activity.