Tetrazines in Inverse-Electron-Demand Diels–Alder Cycloadditions and Their Use in Biology

Abstract

The past 10 years have seen a significant and rapid development in chemoselective reactions for labeling and controlling biological molecules in vitro but also in vivo. Here we review the class of inverse-electron-demand Diels–Alder (iEDDA) cycloadditions that have been re-discovered and developed in recent years as ideal bioorthogonal reactions and that by now play an important role in modern bioconjugation chemistry. We will especially focus on iEDDA reactions between 1,2,4,5-tetrazines and strained dienophiles and we will describe how they can be used for imaging, manipulating, and detecting biological processes.

1 Introduction

2 Inverse-Electron-Demand Diels–Alder (iEDDA) Cycloadditions

3 Synthesis of 1,2,4,5-Tetrazines

4 Synthesis of Strained Dienophiles

5 Applications in Biology

5.1 iEDDA Cycloadditions on Proteins

5.1.1 Fluorescence Labeling of Proteins via Genetic Approaches

5.1.2 Controlling Enzyme Activity in Live Cells via iEDDA Reactions

5.1.3 In vivo Imaging of Proteins via Modified Antibodies and Small Molecules

5.2 iEDDA Reactions on Nucleic Acids

5.3 iEDDA Cycloadditions To Label Glycans and Lipids

5.4 Orthogonal Bioorthogonal Reactions

5.5 Tetrazine Decaging Reactions

6 Recent Development of Other iEDDA Bioorthogonal Reactions

7 Conclusions and Outlook

Key words

bioorthogonal - inverse-electron-demand Diels–Alder cy­cloadditions - tetrazines - strained dienophiles - in vivo chemistries - unnatural amino acids

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