Hongbao Sun; Qinghe Xue; Chang Zhang; Haoxing Wu; Ping Feng
Org. Chem. Front., 2022, 9, 481-498
https://doi.org/10.1039/D1QO01324F

Abstract

Bioorthogonal chemistry is widely used in biological systems and has been trialed in patients, attracting a lot of attention in this century. Tetrazine-based bioorthogonal reactions are essential in chemical biology applications, including cellular labeling, live-cell imaging, diagnosis, drug release, and oncotherapy, due to their tunable rapid reaction kinetics and unique fluorogenic characteristics. However, the scope of de novo tetrazine synthesis is restricted due to the limited supply of commercial starting materials. Therefore, derivatization based on tetrazine scaffold has been used to synthesize various tetrazine derivatives to enhance applications of tetrazine bioorthogonal reactions. Herein, the recent advances in tetrazine scaffold-based derivatizations, including tetrazine skeleton, aromatic substituents and alkyl substituents of tetrazines have been summarized. The advantages and limitations of derivatization methods and applications of developed tetrazine derivatives in biorthogonal chemistry have also been highlighted.