2024/09/19 by Michal Rahm, Patrick Keppel, Veronika Šlachtová +10 · 1 voice
Chemistry · Biochemistry, Genetics and Molecular Biology · #Click Chemistry and Applications #Protein Degradation and Inhibitors #Chemical Synthesis and Analysis
paper · doi:10.1002/anie.202411713
openalex publication_date 2024/09/19 · openalex created_date 2024/09/20 · openalex updated_date 2026/08/04
Abstract Bioorthogonal reactions that enable switching molecular functions by breaking chemical bonds have gained prominence, with the tetrazine‐mediated cleavage of trans ‐cyclooctene caged compounds (click‐to‐release) being particularly noteworthy for its high versatility, biocompatibility, and fast reaction rates. Despite several recent advances, the development of highly reactive tetrazines enabling quantitative elimination from trans ‐cyclooctene linkers remains challenging. In this study, we present the synthesis and application of sulfo‐tetrazines, a class of derivatives featuring phenolic hydroxyl groups with increased acidity constants (p K a ). This unique property leads to accelerated elimination and complete release of the caged molecules within minutes. Moreover, the inclusion of sulfonate groups provides a valuable synthetic handle, enabling further derivatization into sulfonamides, modified with diverse substituents. Significantly, we demonstrate the utility of sulfo‐tetrazines in efficiently activating fluorogenic compounds and prodrugs in living cells, offering exciting prospects for their application in bioorthogonal chemistry.