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Scientific result | Chemistry
Researchers at the Joliot Institute (LMC and LMT at SCBM) have developed two new families of iminosydnones that allow the bio-orthogonal release of electrophilic species. These molecules constitute "building blocks" of click-and-release chemistry, useful for reactions with nucleophilic compounds contained in cells.
The recent Nobel Prize in Chemistry awarded to Carolyn Bertozzi, Karl Barry Sharpless and Morten Peter Meldal for the development of click chemistry and bioorthogonal chemistry confirms the major interest of this young branch of chemistry. It consists in preparing molecular objects by creating (click) and/or breaking (release) bonds between "bricks" thanks to a small number of highly efficient and selective chemical reactions, under conditions compatible with those of a biological environment, notably those of a living organism.
In 2017, a team at SCBM had discovered that certain compounds, iminosydnones (mesoionic reagents) could be reagents of choice for click-and-release reactions. Grafted onto a protein, they react rapidly with cyclic alkynes in biological media to form two products: one from the ligation of the two reaction partners (protein + cyclic alkyne), the other corresponding to the cleavage of the iminosydnone from the protein (SPICC reaction - strain-promoted iminosydnones-cycloalkyne cycloaddition).
In collaboration with the ICSN, I2BC, Iramis, SMBP (UMR 8249) et the New Jersey Institute of Technology, researchers from the laboratories LMC and LMT at SCBM have developed two new families of iminosydnones that allow the bio-orthogonal release of electrophilic species under physiological conditions. In a paper published in JACS, the team describes their synthesis and their reactivity in cycloaddition reactions with constrained alkynes, cyclooctynes (SPICC reaction). These new iminosydnones can be considered as "caged" isocyanates that can be released, on demand, by adding a cyclooctyne, and be particularly useful for the exploration of cellular functions: the released isocyanates will be able to react with molecules that contain a nucleophilic group (as in proteins or metabolites).
One of the next steps may be to chlorinate these iminosydnones to make them even more reactive.
Maxime Ribéraud, Karine Porte, Arnaud Chevalier, Léa Madegard, Aurélie Rachet, Agnès Delaunay-Moisan, Florian Vinchon, Pierre Thuéry, Giovanni Chiappetta, Pier Alexandre Champagne, Grégory Pieters, Davide Audisio, and Frédéric Taran. Fast and Bioorthogonal Release of Isocyanates in Living Cells from Iminosydnones and Cycloalkynes. | JACS, 2023 Feb 1;145(4):2219-2229. https://doi.org/10.1021/jacs.2c09865
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