LAUSR

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.