Derivatization based on tetrazine scaffolds: synthesis of tetrazine derivatives and their biomedical applications

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 scaffolds has been used to synthesize various tetrazine derivatives to enhance the applications of tetrazine bioorthogonal reactions. Herein, the recent advances in tetrazine scaffold-based derivatizations, including tetrazine skeletons, aromatic substituents and alkyl substituents of tetrazines, have been summarized. The advantages and limitations of the derivatization methods and applications of the developed tetrazine derivatives in bioorthogonal chemistry have also been highlighted.