Reversible Conjugate Addition in Thiol‐Mediated Uptake
Abstract Dynamic covalent chemistry involving conjugate addition requires reversibility under specific conditions. In classical systems, reversible Michael addition of thiols is achieved using α‐cyano acrylamides. The more recent oxSTEF reagents introduce β,β‐bissulf(ox)ido enones instead to achieve reversibility of conjugate addition. The objective of this study was to investigate the activity of oxSTEF reagents in the context of thiol‐mediated uptake (TMU) into cells, in comparison as well as in combination with conventional reversible Michael acceptors. Whereas none of tested oxSTEF reagents enables or inhibits TMU significantly, some activate the TMU of conventional α‐cyano acrylamides (cyclic β‐sulfido‐β‐sulfoxido enones), and others activate TMU of α‐helical thioredoxin mimics through intriguing and selective tetrel‐centered dynamic covalent exchange cascades. Activated by an unorthodox oxSTEF Michael acceptor, classical reversible Michael acceptors emerge as the most active monomeric TMU probes known today.
Authors
- Giacomo Renno (ORCID: https://orcid.org/0000-0003-0514-9974)
- Oliver Thorn‐Seshold (ORCID: https://orcid.org/0000-0003-3981-651X)
- Thomas B. Poulsen (ORCID: https://orcid.org/0000-0002-0763-9996)
- Gustav J. Wørmer (ORCID: https://orcid.org/0000-0002-8089-7107)
- Naomi Sakai (ORCID: https://orcid.org/0000-0002-9460-1944)
- Yuheng Zhang (ORCID: https://orcid.org/0000-0001-5396-8283)
- Stefan Matile (ORCID: https://orcid.org/0000-0002-8537-8349)
- Ahmad M. Tamr
Institutions
- University of Geneva (CH)
- Aarhus University (DK)
- Molina Center for Energy and the Environment (US)
- NCCR Chemical Biology - Visualisation and Control of Biological Processes Using Chemistry (CH)
- Hochschule für Technik und Wirtschaft Dresden – University of Applied Sciences (DE)
- Technische Universität Dresden (DE)
Publication Details
- Journal
- Helvetica Chimica Acta
- Published
- 2025-08-28
- DOI
- https://doi.org/10.1002/hlca.202500091
- Citations
- 2
- Primary Topic
- Chemical Synthesis and Analysis
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Novo Nordisk
- Université de Genève
- Novo Nordisk Fonden