A Stimuli‐Responsive Small‐Molecule Metal‐Carrying Prochelator: A Novel Prodrug Design Strategy for Metal Complexes
A Stimuli‐Responsive Small‐Molecule Metal‐Carrying Prochelator: A Novel Prodrug Design Strategy for Metal Complexes
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DOI：
10.1002/anie.202203500
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Chunshun Zhao
中科院分区：
文献类型：
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作者：
Zeqian Huang;Yong Luo;Tao Zhang;Yaqing Ding;Meixu Chen;Jie Chen;Qiuxing Liu;Yanjuan Huang;Chunshun Zhao
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 H2 O2 -responsive small-molecule prochelator, DPBD, based on the strong chelator diethyldithiocarbamate (DTC) and copper. DPBD can carry Cu2+ (DPBD-Cu) and respond to elevated H2 O2 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.
