Unraveling Tetrazine-Triggered Bioorthogonal Elimination Enables Chemical Tools for Ultrafast Release and Universal Cleavage

被引:135
作者
Carlson, Jonathan C. T. [1 ]
Mikula, Hannes [1 ,2 ]
Weissleder, Ralph [1 ,3 ]
机构
[1] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA
[2] Vienna Univ Technol TU Wien, Inst Appl Synthet Chem, A-1040 Vienna, Austria
[3] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA
基金
美国国家卫生研究院; 奥地利科学基金会;
关键词
DIELS-ALDER REACTION; FREE CLICK CHEMISTRY; TRANS-CYCLOOCTENE; DERIVATIVES; ACTIVATION; MECHANISM; STRATEGY; DRUG;
D O I
10.1021/jacs.7b11217
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Recent developments in bond cleavage reactions have expanded the scope of bioorthogonal chemistry beyond click ligation and enabled new strategies for probe activation and therapeutic delivery. These applications, however, remain in their infancy, with further innovations needed to achieve the efficiency required for versatile and broadly useful tools in vivo. Among these chemistries, the tetrazine/trans-cyclooctene click-to-release reaction has exemplary kinetics and adaptability but achieves only partial release and is incompletely understood, which has limited its application. Investigating the mechanistic features of this reaction's performance, we discovered profound pH sensitivity, exploited it with acid-functionalized tetrazines that both enhance and markedly accelerate release, and ultimately uncovered an unexpected dead-end isomer as the reason for poor release. Implementing facile methods to prevent formation of this dead end, we have achieved exceptional efficiency, with essentially complete release across the full scope of physiologic pH, potentiating drug-delivery strategies and expanding the dynamic range of bioorthogonal on/off control.
引用
收藏
页码:3603 / 3612
页数:10
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