Tetrazine‐Triggered Bioorthogonal Cleavage of trans‐Cyclooctene‐Caged Phenols Using a Minimal Self‐Immolative Linker Strategy. (30th August 2022)

• Record Type: Journal Article
• Authors: Keppel, Patrick; Sohr, Barbara; Kuba, Walter; Goldeck, Marion; Skrinjar, Philipp; Carlson, Jonathan C. T.; Mikula, Hannes
• Is Part Of: Chembiochem. Volume 23:Number 20(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-08-30
• Subjects: bioorthogonal chemistry -- click chemistry -- cycloaddition -- elimination -- prodrugs; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.202200363
• Languages: English
• ISSNs: 1439-4227

Abstract

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 750‐fold reduced cytotoxicity compared to the parent drug and achieved in situ activation upon Tz/TCO click‐to‐release. Abstract : Bioorthogonal activation of caged phenols enables strategies to control the function of (bio)molecules in biological environments. While previous methods have been limited by slow click kinetics or insufficient stability, we show that introduction of a self‐immolative linker affords stable trans ‐cyclooctene conjugates, as demonstrated by the design of a prodrug that upon bioorthogonal reaction with tetrazines leads to >200‐fold cytotoxicity.