Sydnones Derivatives as Bioorthogonal Caged Electrophiles for Permanent Fluorescent Labelling – SydFluo

Mesoionic compounds represent an old family of dipoles whose reactivity has been under-exploited since their discovery almost a century ago. Among these compounds, sydnones are undoubtedly the best known and most widely used mesoionics, especially for the synthesis of pyrazoles by thermal cycloaddition reaction with alkynes. Over the last decade, our team has shown that mesoionic compounds can be used instead of other dipoles to develop new click and bioorthogonal reactions. In this context, the SydFluo project aims to explore two mesoionic compounds, sydnonimines and sydnonemethides, which are virtually unknown in the literature. Based on a set of encouraging preliminary results, SydFluo aims to develop new routes to these compounds in order to synthesize new dipoles and to study their reactivity in cycloaddition reactions with cyclooctynes. The syntheses of these new mesoionic compounds will be guided by theoretical calculations that can predict their reactivity. Cycloaddition reactions with these mesoionic compounds generate electrophilic species, isocyanates in the case of sydnonimines and ketenes in the case of sydnonemethides. The project aims to exploit this property to develop new fluorogenic probes allowing permanent, irreversible labelling of cellular compartments. These probes will allow the controlled release of fluorescent electrophiles in a precise organelle that will react with the surrounding proteins. Such tools could find numerous applications in cell imaging and also in proteomics.