title: Gold(I) carbene complexes causing thioredoxin 1 and thioredoxin 2 oxidation as potential anticancer agents.
abstract: Gold(I) complexes with 1,3-substituted imidazole-2-ylidene and benzimidazole-2-ylidene ligands of the type NHC-Au-L (NHC = N-heterocyclic carbene L = Cl or 2-mercapto-pyrimidine) have been synthesized and structurally characterized. The compounds were evaluated for their antiproliferative properties in human ovarian cancer cells sensitive and resistant to cisplatin (A2780S/R), as well in the nontumorigenic human embryonic kidney cell line (HEK-293T), showing in some cases important cytotoxic effects. Some of the complexes were comparatively tested as thioredoxin reductase (TrxR) and glutathione reductase (GR) inhibitors, directly against the purified proteins or in cell extracts. The compounds showed potent and selective TrxR inhibition properties in particular in cancer cell lines. Remarkably, the most effective TrxR inhibitors induced extensive oxidation of thioredoxins (Trxs), which was more relevant in the cancerous cells than in HEK-293T cells. Additional biochemical assays on glutathione systems and reactive oxygen species formation evidenced important differences with respect to the classical cytotoxic Au(I)-phosphine compound auranofin.
authors.affiliation: Fachbereich C, Anorganische Chemie, Bergische Universität Wuppertal, Gaußstraße 20, 42119 Wuppertal, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Schuh
authors.forename: Carolin
authors.initials: C
authors.lastname: Pflüger
authors.forename: Anna
authors.initials: A
authors.lastname: Citta
authors.forename: Alessandra
authors.initials: A
authors.lastname: Folda
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Rigobello
authors.forename: Alberto
authors.initials: A
authors.lastname: Bindoli
authors.forename: Angela
authors.initials: A
authors.lastname: Casini
authors.forename: Fabian
authors.initials: F
authors.lastname: Mohr
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001310:Auranofin / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002457:Cell Extracts; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors; D006046:Gold; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors; D013879:Thioredoxins / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D002457:Cell Extracts; D056831:Coordination Complexes; D007093:Imidazoles; D017382:Reactive Oxygen Species; D001310:Auranofin; D013879:Thioredoxins; D006046:Gold; D005980:Glutathione Reductase; D013880:Thioredoxin-Disulfide Reductase