Bridge Clamp Bis-Tetrazines Stacked by [N]8-π-Interactions and Azido-s-Aryl Tetrazines: New Classes of Doubly Clickable Tetrazines.
Fiche publication
Date publication
octobre 2019
Journal
Angewandte Chemie (International ed. in English)
Auteurs
Membres identifiés du Cancéropôle Est :
Pr DENAT Franck
Tous les auteurs :
Hierso JC, Mboyi CD, Vivier D, Daher A, Fleurat-Lessard P, Cattey H, Devillers C, Bernhard C, Denat F, Roger J
Lien Pubmed
Résumé
Tetrazine core "click-chemistry" is a blooming method for bioorthogonal labeling and crosslinking. We introduce two new classes of doubly clickable s-aryl tetrazines synthesized by Cu-catalyzed cross-coupling. Homocoupling arylation applied to o-brominated s-aryl tetrazines leads to bis-tetrazines structurally-characterized by tetrazine cores arranged "face-to-face". Their previously unseen bridge clamp structure was investigated by DFT. London dispersion forces, which are experimentally evidenced for the first time as [N] 8 -π-stacking interactions, are essential to the conformation. Upon inverse Electron Demand Diels-Alder (iEDDA) cycloaddition the o-biphenyl motif of bis-tetrazines produces a unique structuring stapling tool. The o-azidation of s-aryltetrazines introduces a second proximal intermolecular clickable function that opens the way to double clicking chemistry opportunities. The stepwise facile introduction of fluorophores (coumarin, pyrene) then iEDDA cycloaddition, including bioconjugation to antibodies, was achieved on this class of tetrazines. The Cu-based synthetic toolbox extends to (thio)-etherification, phosphination, trifluoromethylation and the introduction of various bioactive nitrogen-based heterocycles.
Mots clés
Click chemistry, Heteroaromatics, London Dispersion Forces, Tetrazines, iEDDA Cycloaddition
Référence
Angew. Chem. Int. Ed. Engl.. 2019 Oct 23;: