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We describe a versatile and tuneable thiol responsive linker system using thiovinylketones, which relies on the conjugate addition–elimination mechanism of Michael acceptors for the traceless release of therapeutics. In a proof-of-principle study, we translate our findings to exhibit potent thiol-cleavable antibiotic prodrugs and antibody–drug conjugates. [ABSTRACT FROM AUTHOR]

The controlled liberation of molecules from a constructed framework is a subject of profound interest across various chemical fields. It allows for the masking of a molecule's properties and precise deployment upon a single controllable release event. While numerous methodologies have been developed for amines, alcohols, and thiols, approaches for utilising amides as payload-release handles are still in their early stages of development, despite the prevalence of amides in therapeutic compounds and materials. Herein, is presented a comprehensive strategy for the controlled and selective release of a diverse range of amides with stable linkers. The versatility of this approach is demonstrated by its successful application in the targeted release of various amide-containing drugs in their natural form via the use of commonly used trigger motifs, such as dipeptides or glycosides. As a proof of concept, the FDA-approved antibiotic linezolid has been successfully converted into a prodrug form and released selectively only in the presence of the trigger event. Significantly, in its prodrug state, no activity against Mycobacterium tuberculosis was exhibited. Linezolid's full potential was achieved only upon controlled release, where an equipotent efficacy to the free linezolid control was demonstrated, thus emphasising the immense potential of this method., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)