Optimized Tetrazine Derivatives for Rapid Bioorthogonal Decaging in Living Cells
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- 作者：Dr. Xinyuan Fan ; Yun Ge ; Feng Lin ; Yi Yang ; Gong Zhang ; William Shu Ching Ngai ; Zhi Lin ; Siqi Zheng ; Jie Wang ; Dr. Jingyi Zhao ; Dr. Jie Li and Prof. Dr. Peng R. Chen
- 刊名：Angewandte Chemie
- 出版年：2016
- 出版时间：November 2, 2016
- 年：2016
- 卷：128
- 期：45
- 页码：14252-14256
- 全文大小：2183K
- ISSN：1521-3757
文摘
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.