title: 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-PF6 displays a favorable stability that allows it to inhibit TrxR activity without being attacked by blood thiols. In vivo studies reveal that 1-PF6 significantly 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-PF6 does not show systemic anaphylaxis on guinea pigs and localized irritation on rabbits.
authors.affiliation: State Key Laboratory of Synthetic Chemistry, Institute of Functional Materials and Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong (China).
authors.forename: Taotao
authors.initials: T
authors.lastname: Zou
authors.forename: Ching Tung
authors.initials: CT
authors.lastname: Lum
authors.forename: Chun-Nam
authors.initials: CN
authors.lastname: Lok
authors.forename: Wai-Pong
authors.initials: WP
authors.lastname: To
authors.forename: Kam-Hung
authors.initials: KH
authors.lastname: Low
authors.forename: Chi-Ming
authors.initials: CM
authors.lastname: Che
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006046:Gold / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D008697:Methane / Q000031:analogs & derivatives* / Q000737:chemistry; D051379:Mice; D009389:Neovascularization, Pathologic; D011817:Rabbits; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D013880:Thioredoxin-Disulfide Reductase / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008024:Ligands; D013438:Sulfhydryl Compounds; C030011:carbene; D006046:Gold; D013880:Thioredoxin-Disulfide Reductase; D008697:Methane
keywords: N-heterocyclic carbenes; antitumor agents; gold(I); thiol reactivity; thioredoxin reductase (TrxR)