STEFs: Activated Vinylogous Protein‐Reactive Electrophiles

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 inhibito...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2019-03, Vol.58 (11), p.3533-3537
Main Authors: Hansen, Bente K., Loveridge, Christopher J., Thyssen, Stine, Wørmer, Gustav J., Nielsen, Andreas D., Palmfeldt, Johan, Johannsen, Mogens, Poulsen, Thomas B.
Format: Article
Language:English
Subjects:
bioconjugation
Conjugation
cysteine
Organic chemistry
probes
Proteins
proteomics
Selectivity
sulfur
Thioesters
Warheads
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Summary: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. S marks the spot: A new class of activated vinylogous thioesters, called STEFs, were evaluated for use as biological electrophiles. These compounds, for example, enable cysteine‐directed lysine conjugations by consecutive addition–elimination reactions. STEFs, as electrophilic warheads, could find broad use in chemical biology.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201814073