Prodrugs, which remain inert until they are activated under appropriate conditions at the target site, have emerged as an attractive alternative to drugs that lack selectivity and show off-target effects. Prodrugs have traditionally been activated by enzymes, pH or other trigger factors associated with the disease. In recent years, bioorthogonal chemistry has allowed the creation of prodrugs that can be chemically activated with spatio-temporal precision. In particular, tetrazine-responsive bioorthogonal reactions can rapidly activate prodrugs with excellent biocompatibility. This review summarized the recent development of tetrazine bioorthogonal cleavage reaction and great promise for prodrug systems.
In this study, we report the bioorthogonal cleavage of physiologically stable methylene tetrazines bearing an ether or ester linkage in the presence of trans-cyclooctene. Based on this approach, molecules with phenol or carboxylic acid moieties were efficiently released in a controlled manner, which can be effectively applied in living cells. We expect this bioorthogonal cleavage approach can be applied to several biomedical applications, including the development of antibody−drug conjugates, pretargeted prodrug release, and protein activation.
Strongly fluorogenic boron dipyrromethene (BODIPY)-tetrazine probes have been obtained by introducing an alkoxy tetrazine fragment at the boron center. The fluorescence signal from these probes strongly increases by up to 225-fold after reaction with bioorthogonal coupling partners, and the hydrophilicity of probes is improved, such that they are suitable for live-cell imaging.
The front cover picture shows the generation of BODIPY turn‐on probes by introducing alkoxy tetrazines at the boron center of the BODIPY scaffold. This method endows the probes with the high water solubility and endows the bioorthogonal partner—TCO— with strongly fluorogenic properties. Using designed probes to detect TCO‐decorated antibodies on cells provides further insights into their application in live‐cell imaging. More information can be found in the full paper by H. Wu, P. Feng, et al. on page 530 in Issue 6, 2018 (DOI: 10.1002/cbic.201700556).
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