A binuclear gold(I) complex with mixed bridging diphosphine and bis(N-heterocyclic carbene) ligands shows favorable thiol reactivity and inhibits tumor growth and angiogenesis in vivo

Abstract

In the design of anticancer gold(I) complexes with high in vivo efficacy, tuning the thiol reactivity to achieve stability towards blood thiols yet maintaining the thiol reactivity to target cellular thioredoxin reductase (TrxR) is of pivotal importance. Herein we describe a dinuclear gold(I) complex (1-PF6) utilizing a bridging bis(N-heterocyclic carbene) ligand to attain thiol stability and a diphosphine ligand to keep appropriate thiol reactivity. Complex 1-PF6displays a favorable stability that allows it to inhibit TrxR activity without being attacked by blood thiols. In vivo studies reveal that 1-PF6significantly inhibits tumor growth in mice bearing HeLa xenograft and mice bearing highly aggressive mouse B16-F10 melanoma. It inhibits angiogenesis in tumor models and inhibits sphere formation of cancer stem cells in vitro. Toxicology studies indicate that 1-PF6does not show systemic anaphylaxis on guinea pigs and localized irritation on rabbits. It′s in the blood: A binuclear gold(I) complex 1-PF6is stable towards blood thiols and is a tight-binding inhibitor of thioredoxin reductase (TrxR). In vivo antitumor studies show 81-% inhibition of tumor growth in mice with HeLa xenografts and 62-% inhibition of highly aggressive mouse B16-F10 melanoma. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.