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

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 H2O2-responsive small-molecule prochelator, DPBD, based on the strong chelator diethyldithiocarbamate (DTC) and copper. DPBD can carry Cu2+ (DPBD-Cu) and respond to elevated H2O2 levels in tumor cells by releasing DTC, which rapidly chelates Cu2+ 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.

Automated summary

Selective activation of prodrugs is important for reducing the side effects of disease treatment. In this study, a metal-carrying prochelator concept was proposed, which can co-carry a metal ion and chelator within a small-molecule compound and synthesize a bioactive metal complex for targeted therapy. A H2O2-responsive small-molecule prochelator, DPBD, was designed and showed potent antitumor efficacy with low systemic toxicity by releasing chelator DTC and chelating Cu2+.