title: Benzimidazol-2-ylidene gold(I) complexes are thioredoxin reductase inhibitors with multiple antitumor properties.
abstract: Gold(I) complexes such as auranofin have been used for decades to treat symptoms of rheumatoid arthritis and have also demonstrated a considerable potential as new anticancer drugs. The enzyme thioredoxin reductase (TrxR) is considered as the most relevant molecular target for these species. The here investigated gold(I) complexes with benzimidazole derived N-heterocyclic carbene (NHC) ligands represent a promising class of gold coordination compounds with a good stability against the thiol glutathione. TrxR was selectively inhibited by in comparison to the closely related enzyme glutathione reductase, and all complexes triggered significant antiproliferative effects in cultured tumor cells. More detailed studies on a selected complex revealed a distinct pharmacodynamic profile including the high increase of reactive oxygen species formation, apoptosis induction, strong effects on cellular metabolism (related to cell surface properties, respiration, and glycolysis), inhibition of mitochondrial respiration and activity against resistant cell lines.
authors.affiliation: Institute of Pharmaceutical Chemistry, Technische Universität Braunschweig, Beethovenstrasse 55, 38106 Braunschweig, Germany.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Rubbiani
authors.forename: Igor
authors.initials: I
authors.lastname: Kitanovic
authors.forename: Hamed
authors.initials: H
authors.lastname: Alborzinia
authors.forename: Suzan
authors.initials: S
authors.lastname: Can
authors.forename: Ana
authors.initials: A
authors.lastname: Kitanovic
authors.forename: Liliane A
authors.initials: LA
authors.lastname: Onambele
authors.forename: Maria
authors.initials: M
authors.lastname: Stefanopoulou
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Geldmacher
authors.forename: William S
authors.initials: WS
authors.lastname: Sheldrick
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wolber
authors.forename: Aram
authors.initials: A
authors.lastname: Prokop
authors.forename: Stefan
authors.initials: S
authors.lastname: Wölfl
authors.forename: Ingo
authors.initials: I
authors.lastname: Ott
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019069:Cell Respiration / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005978:Glutathione / Q000378:metabolism; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors; D006019:Glycolysis; D006046:Gold; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D010101:Oxygen Consumption / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D056831:Coordination Complexes; D017382:Reactive Oxygen Species; D006046:Gold; D005980:Glutathione Reductase; D013880:Thioredoxin-Disulfide Reductase; D005978:Glutathione