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

被引：21

作者：

Huang, Zeqian ^{[1
]}

Luo, Yong ^{[1
]}

Zhang, Tao ^{[1
]}

Ding, Yaqing ^{[1
]}

Chen, Meixu ^{[1
]}

Chen, Jie ^{[1
]}

Liu, Qiuxing ^{[1
]}

Huang, Yanjuan ^{[1
]}

Zhao, Chunshun ^{[1
]}

机构：

[1] Sun Yat Sen Univ, Sch Pharmaceut Sci, Guangzhou 510006, Peoples R China

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2022年 / 61卷 / 28期

基金：

中国国家自然科学基金;

关键词：

Copper Carriers; Disulfiram; Metal Complexes; Prochelator; Prodrug; OXIDATIVE STRESS; DISULFIRAM; CANCER; COPPER;

D O I：

10.1002/anie.202203500

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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.

引用

页数：11

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