Discovery of bioorthogonal click and release reactions: toward new tools for chemical biology – CLICKREAL

The project involves 3 main steps:
The first one is constructed on our preliminary results; it will be focused on iminosydnones whose capacity to react as mesoionic partner with cycloalkynes has been already established. The second phase of the project will be devoted to mesoionincs in a global sense with the help of computational tools developed during the first phase of the project. Finally, the end of the project aims at evaluating the utility of the discovered reactions in the context of drug release from and antibody-drug conjugate.

We found that fluorosydnones mesoionic compounds undergo ultra-fast click reaction by reactiong more than 1000 times faster than azides with cyclooctynes. This finding will be soon published. Besides this discovery, we synthesed dozen of new mesoionics and screned them for their capacity to react with a Library of dipolarophiles.
Calculations were also carried out to try to understand the reactivity of mesoionics and hopefully to understand the influence of substituents such as fluor on the kinetics.

A publication is under progress on the fluor effect.

Elodie Decuypere, Simon Specklin, Sandra Gabillet, Davide Audisio, Hui Liu, Lucie Plougastel, Sergii Kolodych, Frédéric Taran. Org. Lett., 2015, 17, 362-365.

The CLICKREAL project aims at exploring the reaction of mesoionic compounds with strained alkynes. This proposal is based on preliminary results obtained by our laboratories proving that mesoionics undergo fast [3+2] cycloaddition and retro-Diels-Alder reactions with cycloalkynes. This process recently discovered by our group leads to chemoselective ligation between the two partners and, in the same time, to the release of a fragment molecule. This type of reaction is therefore of strong potential both for chemical biology and nanomedecine since it can be used to develop new reagents for bioconjugation, proteomics or drug release systems. Based on our previous results and on the development of molecular modeling tools, the project envision to explore the basic chemistry of a series of designed mesoionics, to explore their capacity to undergo [3+2] cycloaddition/retro-Diels-Alder reactions with strained cycloalkynes and finally to identify the new chemoselective and bioorthogonal click and release reaction.