Phosphorogenic Iridium(III) bis-Tetrazine Complexes for Bioorthogonal Peptide Stapling, Bioimaging, Photocytotoxic Applications, and the Construction of Nanosized Hydrogels

The dual functionality of 1,2,4,5-tetrazine as a bioorthogonal reactive unit and a luminescence quencher has shaped tetrazine-based probes as attractive candidates for luminogenic labeling of biomolecules in living systems. In this work, three cyclometalated iridium(III) complexes featuring two tetrazine units were synthesized and characterized. Upon photoexcitation, the complexes were non-emissive but displayed up to 3900-fold emission enhancement upon the inverse electron-demand Diels-Alder (IEDDA) [4+2] cycloaddition with (1R,8S,9s)-bicyclo[6.1.0]non-4-yne (BCN) substrates. The rapid reaction kinetics (k(2) up to 1.47x10(4) M-1 s(-1)) of the complexes toward BCN substrates allowed effective peptide labeling. The complexes were also applied as live cell bioimaging reagents and photocytotoxic agents. One of the complexes was utilized in the preparation of luminescent nanosized hydrogels that exhibited interesting cargo delivery properties.

Automated summary

1,2,4,5-tetrazine functions as both a bioorthogonal reactive unit and a luminescence quencher, making it a desirable candidate for luminogenic labeling in living systems. This study synthesized and characterized three cyclometalated iridium(III) complexes with two tetrazine units, which exhibited high reaction kinetics towards specific substrates, allowing effective peptide labeling. These complexes were also applied for live cell bioimaging and photocytotoxicity, and one of them was used to prepare luminescent nanosized hydrogels with interesting cargo delivery properties.