Iridium(III) bis-Nitrone Complexes as Innovative Phosphorogenic Reagents for Bioimaging and Phototherapeutics

Bioorthogonal chemical reactions have emerged as useful tools for labeling biomolecules in living systems. Nitrones are a relatively new bioorthogonal system that show high reactivity toward strained cyclooctynes via the strain-promoted alkyne-nitrone cycloaddition (SPANC) reaction. Luminescent transition metal complexes can be made non-emissive by the modification with a nitrone moiety due to the efficient non-radiative decay caused by the C=N photoisomerization. However, the complexes exhibit intense and long-lived emission upon reaction with strained alkynes such as (1R,8S,9s)-bicyclo[6.1.0]nonyne (BCN). In this work, a series of cyclometalated iridium(III) complexes functionalized with two nitrone units on the bipyridine ligand has been designed as novel phosphorogenic bioorthogonal reagents for bioimaging and phototherapy. Upon reaction with BCN substrates, the complexes displayed significant emission enhancement and lifetime extension. Importantly, the complexes showed a higher reaction rate toward a bis-cyclooctyne derivative containing a TEG linker (bis-BCN) compared with its monomeric counterpart. Additionally, the cellular uptake, imaging and photocytotoxic properties of the complexes were explored. A peptide model modified with two BCN units was also successfully stapled by a bis-nitrone complex. The physiochemical and biological properties of the stapled peptide will be further investigated.