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

摘要

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 boolean AND N boolean AND N)(N,N'-nBu(2)NHC)](CF3SO3) (Pd1d, HC boolean AND N boolean AND N = 6-phenyl-2,2'-bipyridine, N,N'-nBu(2)NHC = N,N'di-n-butylimidazolylidene), displays potent killing activity toward cancer cell lines (IC50 = 0.09-0.5 mm) but is less cytotoxic toward a normal human fibroblast cell line (CCD-19Lu, IC50 = 11.8 mm). In vivo anticancer studies revealed that Pd1d significantly inhibited tumor growth in a nude mice model. Proteomics data and in vitro biochemical assays reveal that Pd1d exerts anticancer effects, including inhibition of an epidermal growth factor receptor pathway, induction of mitochondrial dysfunction, and antiangiogenic activity to endothelial cells.