Thiol-thiol cross-clicking using bromo-ynone reagents

Marvin Nicque, Jan H. Meffert, Diederick Maes, Kevin Bevernaege, Mehwish Iftikhar, Olivier Zwaenepoel, Jan Gettemans, Annemieke Madder and Johan M. Winne ()
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Marvin Nicque: Ghent University
Jan H. Meffert: Ghent University
Diederick Maes: Ghent University
Kevin Bevernaege: Ghent University
Mehwish Iftikhar: Ghent University
Olivier Zwaenepoel: Ghent University
Jan Gettemans: Ghent University
Annemieke Madder: Ghent University
Johan M. Winne: Ghent University

Nature Communications, 2025, vol. 16, issue 1, 1-9

Abstract: Abstract Thiols are used in many click reactions, and are also excellent platforms for biomolecular click or bioconjugation reactions. The direct cross-coupling of two thiols is an attractive biomimetic concept for click chemistry, but leads to statistical mixtures of homo- and heterodimers. Here, we introduce a novel class of thiol-click reagents, bromo-ynones, where the kinetic differentiation between the first and second thiol addition onto these reagents facilitates a stepwise one-pot cross-clicking of two distinct thiols in aqueous media, without the need for intermediate isolation or purification. The two thiols are linked through a single carbon atom, mimicking a disulfide bridge. We demonstrate the use of bromo-ynones in the synthesis of various cross-coupled thiols, including small molecule drugs, fluorophores, carbohydrates, peptides and proteins, including an example of a protein-protein heterodimer. The resulting adducts are robust under physiological conditions and by judicious choice of the bromo-ynone reagent, the adducts can be stable even in the presence of excess free thiols.

Date: 2025
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DOI: 10.1038/s41467-025-61682-5

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