A Stimuli‐Responsive Small‐Molecule Metal‐Carrying Prochelator: A Novel Prodrug Design Strategy for Metal Complexes

Abstract Selective activation of prodrugs is an important approach to reduce the side effects of disease treatment. We report a prodrug design concept for metal complexes, termed “metal‐carrying prochelator”, which can co‐carry a metal ion and chelator within a single small‐molecule compound and remain inert until it undergoes a specifically triggered intramolecular chelation to synthesize a bioactive metal complex in situ for targeted therapy. As a proof‐of‐concept, we designed a H 2 O 2 ‐responsive small‐molecule prochelator, DPBD, based on the strong chelator diethyldithiocarbamate (DTC) and copper. DPBD can carry Cu 2+ (DPBD‐Cu) and respond to elevated H 2 O 2 levels in tumor cells by releasing DTC, which rapidly chelates Cu 2+ from DPBD‐Cu affording a DTC–copper complex with high cytotoxicity, realizing potent antitumor efficacy with low systemic toxicity. Thus, with its unique intramolecularly triggered activation mechanism, this concept based on a small‐molecule metal‐carrying prochelator can help in the prodrug design of metal complexes.