The Emerging Role of Tetrazines in Drug‐Activation Chemistries

Abstract

Traditionally, prodrug activation has been limited to enzymatic triggers or gross physiological aberrations, such as pH, that offer low selectivity and control over dosage. In recent years, the field of prodrug activation chemistry has been transformed by the use of bioorthogonal reactions that can be carried out under biological conditions at sub‐millimolar concentrations, with the tetrazine‐mediated inverse electron demand Diels–Alder reaction amongst the most recognised. Their high reaction rates, chemoselectivity and excellent biocompatibility make tetrazines ideal small molecules for activating prodrugs. Recently the tetrazine moiety has been used as a prodrug for a pyridazine thus broadening the scope of prodrug systems. This article discusses the concept of using tetrazines as small‐molecule activators for prodrugs, and provides an overview of tetrazine‐based prodrug systems, with a particular focus on the recently reported prodrug–prodrug activation strategy.

Transition‐Metal‐Mediated versus Tetrazine‐Triggered Bioorthogonal Release Reactions: Direct Comparison and Combinations Thereof

“…Another example showed that the chemistry can be used for chemically‐induced control over T‐cell activation by bioorthogonal deprotection of TCO‐caged epitopes . In addition to the strained TCO, vinyl ethers, benzonorbornadienes and 3‐isocyanopropyl groups were employed as alternative dienophiles in tetrazine‐promoted deprotection reactions …”

Isonitrile-responsive and bioorthogonally removable tetrazine protecting groups

“…3,4 These reactions have opened unprecedented possibilities in chemical biology and drug delivery. 5,6 Dissociative bioorthogonal chemistry has been applied to the on-demand dissolution of polymers and micelles, 7-9 site-specic actuation of prodrugs, [10][11][12] and control of enzyme activity in vivo. [13][14][15] Although a growing number of "click-to-release" reactions [16][17][18][19][20][21][22][23] has provided a solid foundation for applications in the life sciences, extending the reaction scope will be necessary to access the full range of capabilities.…”

Fluorogenic Bifunctional trans‐Cyclooctenes as Efficient Tools for Investigating Click‐to‐Release Kinetics

“…Bioorthogonal chemistry is broadening its scope to include bond cleavage reactions alongside known ligation methods, with many new reactions steadily emerging in this area . Among these is the inverse electron demand Diels–Alder (IEDDA) pyridazine elimination reaction, the first of the bioorthogonal processes known as “click‐to‐release” (Figure A).…”