Biological and Medicinal Chemistry

Tetrazine-Triggered Bioorthogonal Cleavage of trans-Cyclooctene-Caged Phenols Using a Minimal Self-Immolative Linker Strategy

Authors

Abstract

Bond-cleavage reactions triggered by bioorthogonal tetrazine ligation have emerged as strategies to chemically control the function of (bio)molecules and achieve activation of prodrugs in living systems. While most of these approaches make use of caged amines, current methods for the release of phenols are limited by unfavorable reaction kinetics or insufficient stability of the Tz-responsive reactants. To address this issue, we have implemented a self-immolative linker that enables the connection of cleavable trans-cyclooctenes (TCO) and phenols via carbamate linkages. Based on detailed investigation of the reaction mechanism with several Tz, revealing up to 96% elimination after 2 hours, we have developed a TCO-caged prodrug with 700-fold reduced cytotoxicity compared to the parent drug and achieved efficient in situ activation upon Tz/TCO click-to-release.

Content

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Supplementary material

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Supporting Information
Details on general methods, synthesis, release experiments and cell viability assays. Copies of NMR spectra, chromatograms, and MS data.