Exploiting the Potential of Iridium(III) bis-Nitrone Complexes as Phosphorogenic Bifunctional Reagents for Phototheranostics

Nitrone exhibits remarkable versatility and applicability in bioorthogonal labeling due to its high reactivity with strained alkynes via the strain-promoted alkyne−nitrone cycloaddition (SPANC) reaction. In this work, cyclometalated iridium(III) complexes bearing two nitrone units were designed as novel phosphorogenic bioorthogonal reagents for bioimaging and phototherapeutics. The complexes showed efficient emission quenching, which is attributed to a nonradiative decay pathway via the low-lying T₁/S₀ minimum energy crossing point. However, they displayed significant emission enhancement and lifetime extension upon reaction with (1R,8S,9s)-bicyclo[6.1.0]non-4-yne (BCN) derivatives. In particular, they showed a remarkably higher reaction rate toward a bis-cyclooctyne derivative (bis-BCN) compared with its monomeric counterpart (mono-BCN). Cellular studies revealed higher photocytotoxicity of the complexes in bis-BCN-pretreated cells, which is ascribed to the enhanced singlet oxygen (¹O₂) photosensitization resulting from the elimination of the nitrone-associated quenching pathway. The cross-linking properties and enhanced reactivity of the complexes make them highly promising candidates for the development of photofunctional hydrogels and stapled/cyclized peptides.