Fast and Bioorthogonal Release of Isocyanates in Living Cells from Iminosydnones and Cycloalkynes
Document Type
Article
Publication Date
2-1-2023
Abstract
Bioorthogonal click-and-release reactions are powerful tools for chemical biology, allowing, for example, the selective release of drugs in biological media, including inside animals. Here, we developed two new families of iminosydnone mesoionic reactants that allow a bioorthogonal release of electrophilic species under physiological conditions. Their synthesis and reactivities as dipoles in cycloaddition reactions with strained alkynes have been studied in detail. Whereas the impact of the pH on the reaction kinetics was demonstrated experimentally, theoretical calculations suggest that the newly designed dipoles display reduced resonance stabilization energies compared to previously described iminosydnones, explaining their higher reactivity. These mesoionic compounds react smoothly with cycloalkynes under physiological, copper-free reaction conditions to form a click pyrazole product together with a released alkyl- or aryl-isocyanate. With rate constants up to 1000 M-1 s-1, this click-and-release reaction is among the fastest described to date and represents the first bioorthogonal process allowing the release of isocyanate electrophiles inside living cells, offering interesting perspectives in chemical biology.
Identifier
85146554408 (Scopus)
Publication Title
Journal of the American Chemical Society
External Full Text Location
https://doi.org/10.1021/jacs.2c09865
e-ISSN
15205126
ISSN
00027863
PubMed ID
36656821
First Page
2219
Last Page
2229
Issue
4
Volume
145
Grant
ANR-11-IDEX-0003-02
Fund Ref
Agence Nationale de la Recherche
Recommended Citation
Ribéraud, Maxime; Porte, Karine; Chevalier, Arnaud; Madegard, Léa; Rachet, Aurélie; Delaunay-Moisan, Agnès; Vinchon, Florian; Thuéry, Pierre; Chiappetta, Giovanni; Champagne, Pier Alexandre; Pieters, Grégory; Audisio, Davide; and Taran, Frédéric, "Fast and Bioorthogonal Release of Isocyanates in Living Cells from Iminosydnones and Cycloalkynes" (2023). Faculty Publications. 1979.
https://digitalcommons.njit.edu/fac_pubs/1979