Published on Journal of The American Chemical Society (9 September 2024)
Author(s): Eunice Chiu-Lam Mak, Ziyong Chen, Lawrence Cho-Cheung Lee, Peter Kam-Keung Leung, Alex Man-Hei Yip, Justin Shum, Shek-Man Yiu, Vivian Wing-Wah Yam*, Kenneth Kam-Wing Lo*
Abstract
Cross-linking strategies have found wide applications in chemical biology, enabling the labeling of biomolecules and monitoring of protein–protein interactions. 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, four cyclometalated iridium(III) polypyridine complexes functionalized with two nitrone units were designed as novel phosphorogenic bioorthogonal reagents for bioimaging and phototherapeutics. The complexes showed efficient emission quenching, which is attributed to an efficient nonradiative decay pathway via the low-lying T1/S0 minimum energy crossing point (MECP), as revealed by computational studies. However, the complexes 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). Live-cell imaging and (photo)cytotoxicity studies revealed higher photocytotoxicity 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. Importantly, the cross-linking properties and enhanced reactivity of the complexes make them highly promising candidates for the development of hydrogels and stapled/cyclized peptides, offering intriguing photophysical, photochemical, and biological properties. Notably, a nanosized hydrogel (2-gel) demonstrated potential as a drug delivery system, while a stapled peptide (2-bis-pDIKK) exhibited p53-Mdm2 inhibitory activity related to apoptosis and a cyclized peptide (2-bis-RGD) showed cancer selectivity.
