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...

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Bibliographic Details
Published in:Angewandte Chemie 2016-09, Vol.128 (39), p.12114-12118
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:
Antiangiogenics
Anticancer properties
Antitumor agents
Biocompatibility
Carbenes
Chemistry
Cytotoxicity
Endothelial cells
Epidermal growth factor
Growth factors
In vivo methods and tests
Mitochondria
N-Heterocyclische Carbene
Palladium
PD-1 protein
Proteomics
Proteomik
Thiolreaktivität
Thiols
Toxicity
Tumor cell lines
Tumors
Tumortherapeutika
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Summary: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. Stabil gegen Tumoren: [Pd(C^N^N)(NHC)]+‐Komplexe zeigen exzellente Stabilität in vitro und in wässrigen Lösungen physiologischer Thiole. Diese Eigenschaft ermöglicht den Komplexen eine wirkungsvolle In‐vitro‐Zytotoxizität gegen Krebszellen und In‐vitro‐Angiogenese in subzytotoxischen Konzentrationen sowie eine effektive Antitumoraktivität gegen Tumorxenografts in Nacktmäusen ohne beobachtbare Toxizität.
ISSN:0044-8249
1521-3757
DOI:10.1002/ange.201602814