Bioorthogonal Activation of Dual Catalytic and Anti‐Cancer Activities of Organogold(I) Complexes in Living Systems

Controllably activating the bio‐reactivity of metal complexes in living systems is challenging but highly desirable because it can minimize off‐target bindings and improve spatiotemporal specificity. Herein, we report a new bioorthogonal activation approach by employing Pd(II)‐triggered transmetallation reactions to conditionally activate the bio‐reactivity of NHC–Au(I)–phenylacetylide complexes (1 a) in vitro and in vivo. A combination of 1H NMR, LC‐MS, DFT calculation and fluorescence screening assays reveals that 1 a displays a reasonable stability against biological thiols, but its phenylacetylide ligand can be efficiently transferred to Pd(II), leading to in situ formation of labile NHC–Au(I) species that is catalytically active inside living cells and zebrafish, and can meanwhile effectively suppress the activity of thioredoxin reductase, potently inhibit the proliferation of cancer cells and efficiently suppress angiogenesis in zebrafish models. A novel bioorthogonal activation approach based on Pd(II)‐mediated transmetallation was developed to controllably activate stable organometallic NHC–gold(I)–phenylacetylide complex. The gold(I) complex, upon transmetallation activation, can catalyze alkyne π‐bond activations and can meanwhile potently inhibit thioredoxin reductase and induce cytotoxicity towards cancer cells in vitro and in vivo with high spatiotemporal selectivity.