期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 55, 期 45, 页码 14046-14050出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201608009
关键词
amino acids; decaging; Diels-Alder reactions; protein activation; protein engineering
资金
- National Key Research and Development Program [2016YFA0501500]
- National Natural Science Foundation of China [21225206, 21432002, 21521003]
- Center for Life Sciences (CLS)
- China Postdoctoral Science Foundation [2016M591004]
The inverse-electron-demand Diels-Alder (iDA) reaction has recently been repurposed as a bioorthogonal decaging reaction by accelerating the elimination process after an initial cycloaddition between trans-cyclooctene (TCO) and tetrazine (TZ). Herein, we systematically surveyed 3,6-substituted TZ derivatives by using a fluorogenic TCO-coumarin reporter followed by LC-MS analysis, which revealed that the initial iDA cycloaddition step was greatly accelerated by electron-withdrawing groups (EWGs) while the subsequent elimination step was strongly suppressed by EWGs. In addition, smaller substituents facilitated the decaging process. These findings promoted us to design and test unsymmetric TZs bearing an EWG group and a small non-EWG group at the 3- and 6-position, respectively. These TZs showed remarkably enhanced decaging rates, enabling rapid iDA-mediated protein activation in living cells.
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