Cyclometalated Palladium(II) N‐Heterocyclic Carbene Complexes: Anticancer Agents for Potent In Vitro Cytotoxicity and In Vivo Tumor Growth Suppression

Palladium(II) complexes are generally reactive toward substitution/reduction, and their biological applications are seldom explored. A new series of palladium(II) N‐heterocyclic carbene (NHC) complexes that are stable in the presence of biological thiols are reported. A representative complex, [Pd(C^N^N)(N,N′‐nBu₂NHC)](CF₃SO₃) ( Pd1 d , HC^N^N=6‐phenyl‐2,2′‐bipyridine, N,N′‐nBu₂NHC=N,N′‐di‐n‐butylimidazolylidene), displays potent killing activity toward cancer cell lines (IC₅₀=0.09–0.5 μm ) but is less cytotoxic toward a normal human fibroblast cell line (CCD‐19Lu, IC₅₀=11.8 μm ). In vivo anticancer studies revealed that Pd1 d significantly inhibited tumor growth in a nude mice model. Proteomics data and in vitro biochemical assays reveal that Pd1 d exerts anticancer effects, including inhibition of an epidermal growth factor receptor pathway, induction of mitochondrial dysfunction, and antiangiogenic activity to endothelial cells.