Unraveling tetrazine-triggered bioorthogonal elimination enables chemical tools for ultrafast release and universal cleavage,Journal of the American Chemical Society

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Unraveling tetrazine-triggered bioorthogonal elimination enables chemical tools for ultrafast release and universal cleavage
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2018-01-31 , DOI: 10.1021/jacs.7b11217
Jonathan C T Carlson ₁ , Hannes Mikula _{1,

2} , Ralph Weissleder _{1,

3}

Affiliation

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.

中文翻译：

解开四嗪触发的生物正交消除使化学工具能够实现超快释放和普遍裂解

键裂解反应的最新发展已将生物正交化学的范围扩大到点击连接之外，并为探针激活和治疗递送提供了新的策略。然而，这些应用仍处于起步阶段，需要进一步创新以实现体内多功能和广泛有用的工具所需的效率。在这些化学反应中，四嗪/反式环辛烯点击释放反应具有示范性的动力学和适应性，但仅实现了部分释放且尚未完全了解，限制了其应用。研究该反应性能的机械特征，我们发现了深刻的 pH 敏感性，将其与酸官能化的四嗪一起使用，既增强又显着加速释放，并最终发现了一个意想不到的死端异构体，这是释放不良的原因。通过实施简单的方法来防止这种死胡同的形成，我们取得了非凡的效率，在整个生理 pH 范围内基本上完全释放，增强了药物递送策略并扩大了生物正交开/关控制的动态范围。

更新日期：2018-01-31

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