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STEFs: Activated Vinylogous Protein‐Reactive Electrophiles
Author(s) -
Hansen Bente K.,
Loveridge Christopher J.,
Thyssen Stine,
Wørmer Gustav J.,
Nielsen Andreas D.,
Palmfeldt Johan,
Johannsen Mogens,
Poulsen Thomas B.
Publication year - 2019
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201814073
Subject(s) - electrophile , chemistry , thiol , amine gas treating , combinatorial chemistry , conjugate , reactivity (psychology) , covalent bond , stereochemistry , biochemistry , organic chemistry , medicine , mathematical analysis , alternative medicine , mathematics , pathology , catalysis
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.