title: NHC gold halide complexes derived from 4,5-diarylimidazoles: synthesis, structural analysis, and pharmacological investigations as potential antitumor agents.
abstract: A series of novel neutral NHC gold halide complexes derived from 4,5-diarylimidazoles were synthesized, characterized, and analyzed for biological effects. High growth inhibitory effects in MCF-7 and MDA-MB 231 breast cancer as well as HT-29 colon cancer cell lines depended on the presence of the C4,C5-standing aromatic rings. Methoxy groups at these rings did not change the growth inhibitory properties, while F-substituents in the ortho-position (5d) increased the activity in MCF-7 and MDA-MB 231 cells. The substituents at the nitrogen atoms and the oxidation state of the metal play a subordinate role. The most active bromo[1,3-diethyl-4,5-bis(2-fluorophenyl)-1,3-dihydro-2H-imidazol-2-ylidene]gold(I) (5d) was distinctly more active than cisplatin. All complexes caused thioredoxin reductase (TrxR) inhibition (EC50=374-1505 nM) distinctly lower than auranofin (EC50=18.6 nM) excluding this enzyme as main target. Because of the low nuclear content, a participation of DNA interaction on the mode of action is very unlikely. The missing ER binding and the missing correlation of growth inhibition and inactivation of COX enzymes exclude these targets, too.
authors.affiliation: Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Strasse, 2+4, 14195 Berlin, Germany.
authors.forename: Wukun
authors.initials: W
authors.lastname: Liu
authors.forename: Kerstin
authors.initials: K
authors.lastname: Bensdorf
authors.forename: Maria
authors.initials: M
authors.lastname: Proetto
authors.forename: Ulrich
authors.initials: U
authors.lastname: Abram
authors.forename: Adelheid
authors.initials: A
authors.lastname: Hagenbach
authors.forename: Ronald
authors.initials: R
authors.lastname: Gust
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006046:Gold; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D050607:Organogold Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000378:metabolism; D013329:Structure-Activity Relationship; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D016861:Cyclooxygenase Inhibitors; D007093:Imidazoles; D050607:Organogold Compounds; D011960:Receptors, Estrogen; C570542:bromo(1,3-diethyl-4,5-bis(2-fluorophenyl)-1,3-dihydro-2H-imidazol-2-ylidene)gold(I); D006046:Gold; D004247:DNA; D013880:Thioredoxin-Disulfide Reductase