A Stimuli‐Responsive Small‐Molecule Metal‐Carrying Prochelator: A Novel Prodrug Design Strategy for Metal Complexes
Zeqian Huang, Yong Luo, Tao Zhang, Yaqing Ding, Meixu Chen, Jie Chen, Qiuxing Liu, Yanjuan Huang, Chunshun Zhao
Abstract
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.