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

• Published in: Angewandte Chemie International Edition 2016-09, Vol.55 (39), p.11935-11939
• Main Authors: Fong, Tommy Tsz-Him, Lok, Chun-Nam, Chung, Clive Yik-Sham, Fung, Yi-Man Eva, Chow, Pui-Keong, Wan, Pui-Ki, Che, Chi-Ming
• Format: Article
• Language: English
• Subjects: Animals; Antiangiogenics; anticancer agents; Anticancer properties; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antitumor agents; Biocompatibility; Carbenes; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Coordination Complexes - therapeutic use; Cytotoxicity; Endothelial cells; Epidermal growth factor; Growth factors; Humans; In vivo methods and tests; Methane - analogs & derivatives; Methane - chemistry; Methane - pharmacology; Methane - therapeutic use; Mice, Nude; Mitochondria; N-heterocyclic carbenes; Neoplasms - drug therapy; Neoplasms - pathology; Palladium; Palladium - chemistry; Palladium - pharmacology; Palladium - therapeutic use; PD-1 protein; Proteomics; thiol reactivity; Thiols; Toxicity; Tumor cell lines; Tumors
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201602814

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. Stable antitumor agent: [Pd(C^N^N)(NHC)]+ complexes demonstrate excellent stability in vitro and in aqueous solutions containing physiological thiols. This may allow the complexes to show potent in vitro cytotoxicity against cancer cells and in vitro angiogenesis at sub‐cytotoxic concentrations, as well as effective in vivo anticancer activities toward tumor xenografts in nude mice with no observable toxicity.