Uncovering the Key Role of Distortion in Bioorthogonal Tetrazine Tools That Defy the Reactivity/Stability Trade-Off.
Uncovering the Key Role of Distortion in Bioorthogonal Tetrazine Tools That Defy the Reactivity/Stability Trade-Off.
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DOI：
10.1021/jacs.2c01056
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发表时间：
2022-05-11
影响因子：
15
通讯作者：
Mikula, Hannes
中科院分区：
文献类型：
--
作者：
Svatunek, Dennis;Wilkovitsch, Martin;Hartmann, Lea;Houk, K. N.;Mikula, Hannes
四嗪/反式环辛烯连接因其出色的反应动力学而在生物正交工具箱中脱颖而出，使多种分子技术在体外和生命系统中成为可能。高反应性的2-吡啶基取代的四嗪已经成为在非常低的浓度下用于时间关键工艺和选择性反应的现有技术。人们普遍认为，这些化学工具的增强的反应性归因于杂芳基取代基的吸电子效应。相比之下，我们发现观察到的反应速率太高，无法在此基础上解释。对这一现象的计算研究表明，四嗪分子内的排斥作用引起的畸变在加速环加成反应中起着关键作用。我们发现，四嗪在生物介质中的有限稳定性与取代基的吸电子效应密切相关，而分子内排斥增加了反应性而不降低稳定性。这些基本的见解揭示了迄今为止被忽视的机制方面，管理的反应性/稳定性权衡四嗪在生理相关的环境中，从而提供了一种新的策略，可以促进这些生物正交工具的合理设计。
The tetrazine/trans-cyclooctene ligation stands out from the bioorthogonal toolbox due to its exceptional reaction kinetics, enabling multiple molecular technologies in vitro and in living systems. Highly reactive 2-pyridyl-substituted tetrazines have become state of the art for time-critical processes and selective reactions at very low concentrations. It is widely accepted that the enhanced reactivity of these chemical tools is attributed to the electron-withdrawing effect of the heteroaryl substituent. In contrast, we show that the observed reaction rates are way too high to be explained on this basis. Computational investigation of this phenomenon revealed that distortion of the tetrazine caused by intramolecular repulsive N–N interaction plays a key role in accelerating the cycloaddition step. We show that the limited stability of tetrazines in biological media strongly correlates with the electron-withdrawing effect of the substituent, while intramolecular repulsion increases the reactivity without reducing the stability. These fundamental insights reveal thus far overlooked mechanistic aspects that govern the reactivity/stability trade-off for tetrazines in physiologically relevant environments, thereby providing a new strategy that may facilitate the rational design of these bioorthogonal tools.
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