Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
Chem Soc Rev. 2017 Aug 14;46(16):4895-4950. doi: 10.1039/c7cs00184c.
The emerging inverse electron demand Diels-Alder (IEDDA) reaction stands out from other bioorthogonal reactions by virtue of its unmatchable kinetics, excellent orthogonality and biocompatibility. With the recent discovery of novel dienophiles and optimal tetrazine coupling partners, attention has now been turned to the use of IEDDA approaches in basic biology, imaging and therapeutics. Here we review this bioorthogonal reaction and its promising applications for live cell and animal studies. We first discuss the key factors that contribute to the fast IEDDA kinetics and describe the most recent advances in the synthesis of tetrazine and dienophile coupling partners. Both coupling partners have been incorporated into proteins for tracking and imaging by use of fluorogenic tetrazines that become strongly fluorescent upon reaction. Selected notable examples of such applications are presented. The exceptional fast kinetics of this catalyst-free reaction, even using low concentrations of coupling partners, make it amenable for in vivo radiolabelling using pretargeting methodologies, which are also discussed. Finally, IEDDA reactions have recently found use in bioorthogonal decaging to activate proteins or drugs in gain-of-function strategies. We conclude by showing applications of the IEDDA reaction in the construction of biomaterials that are used for drug delivery and multimodal imaging, among others. The use and utility of the IEDDA reaction is interdisciplinary and promises to revolutionize chemical biology, radiochemistry and materials science.
新兴的逆电子需求 Diels-Alder（IEDDA）反应以其无与伦比的动力学、出色的正交性和生物相容性而区别于其他生物正交反应。随着新型亲二烯体和最佳四嗪偶联物的最新发现，人们现在开始关注 IEDDA 方法在基础生物学、成像和治疗中的应用。在这里，我们回顾了这种生物正交反应及其在活细胞和动物研究中的有前途的应用。我们首先讨论了促成快速 IEDDA 动力学的关键因素，并描述了四嗪和亲二烯体偶联物合成的最新进展。这两种偶联物都已被整合到蛋白质中，用于通过使用反应后具有强荧光性的荧光四嗪进行跟踪和成像。介绍了此类应用的一些显著例子。即使使用低浓度的偶联物，该催化剂免费反应的出色快速动力学使其适用于使用前靶向方法进行体内放射性标记，我们也讨论了这一点。最后，IEDDA 反应最近在生物正交去封闭中找到了用于在功能获得策略中激活蛋白质或药物的用途。我们最后通过展示 IEDDA 反应在构建用于药物输送和多模式成像等的生物材料中的应用来说明这一点。IEDDA 反应的使用和实用性是跨学科的，有望彻底改变化学生物学、放射化学和材料科学。
