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Angew Chem Int Ed Engl. 2019 Mar 11;58(11):3533-3537. doi: 10.1002/anie.201814073. Epub 2019 Feb 7.

STEFs: Activated Vinylogous Protein-Reactive Electrophiles.

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Department of Chemistry, Aarhus University, Langelandsgade 140, 8000, Aarhus C, Denmark.
Department of Forensic Medicine, Aarhus University, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark.
Department of Clinical Medicine-Research Unit for Molecular Medicine, Aarhus University hospital, Palle Juul-Jensens Boulevard 82, 8200, Aarhus N, Denmark.


Reported here is the synthesis of a class of semi-oxamide vinylogous thioesters, designated STEFs, and the use of these agents as new electrophilic warheads. This work includes preparation of simple probes that contain this reactive motif as well as its installation on a more complex kinase inhibitor scaffold. A key aspect of STEFs is their reactivity towards both thiol and amine groups. Shown here is that amine conjugations in peptidic and proteinogenic samples can be facilitated by initial, fast conjugation to proximal thiol residues. Evidence that both the selectivity and the reactivity can be tuned by the structure of STEFs is provided, and given the unique ability of this functionality to conjugate by an addition-elimination mechanism, STEFs are electrophilic warheads that could find broad use in chemical biology.


bioconjugation; cysteine; probes; proteomics; sulfur


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