title: Ferrocenyl-Coupled N-Heterocyclic Carbene Complexes of Gold(I): A Successful Approach to Multinuclear Anticancer Drugs.
abstract: Four gold(I) carbene complexes featuring 4-ferrocenyl-substituted imidazol-2-ylidene ligands were investigated for antiproliferative and antivascular properties. They were active against a panel of seven cancer cell lines, including multidrug-resistant ones, with low micromolar or nanomolar IC50(72 h) values, according to their lipophilicity and cellular uptake. The delocalized lipophilic cationic complexes 8 and 10 acted by increasing the reactive oxygen species in two ways: through a genuine ferrocene effect and by inhibiting the thioredoxin reductase. Both complexes gave rise to a reorganization of the F-actin cytoskeleton in endothelial and melanoma cells, associated with a G1 phase cell cycle arrest and a retarded cell migration. They proved antiangiogenic in tube formation assays with endothelial cells and vascular-disruptive on real blood vessels in the chorioallantoic membrane of chicken eggs. Biscarbene complex 10 was also tolerated well by mice where it led to a volume reduction of xenograft tumors by up to 80 %.
authors.affiliation: Organic Chemistry Laboratory, University Bayreuth, Universitätsstrasse 30, 95447, Bayreuth, Germany.
authors.forename: Julienne K
authors.initials: JK
authors.lastname: Muenzner
authors.affiliation: Organic Chemistry Laboratory, University Bayreuth, Universitätsstrasse 30, 95447, Bayreuth, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Biersack
authors.affiliation: Organic Chemistry Laboratory, University Bayreuth, Universitätsstrasse 30, 95447, Bayreuth, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Albrecht
authors.affiliation: Organic Chemistry Laboratory, University Bayreuth, Universitätsstrasse 30, 95447, Bayreuth, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Rehm
authors.affiliation: Organic Chemistry Laboratory, University Bayreuth, Universitätsstrasse 30, 95447, Bayreuth, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Lacher
authors.affiliation: Lehrstuhl für Anorganische Chemie I, Universität Bayreuth, Universitätsstrasse 30, 95447, Bayreuth, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Milius
authors.affiliation: Department of Pharmacokinetics, Toxicology, and Targeting, University of Groningen, Antonius Deusinglaan 1, 9713, Groningen, The Netherlands.|School of Chemistry, Cardiff University, Main Building, CF10 3AT, Cardiff, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Casini
authors.affiliation: Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, Beethovenstrasse 55, 38106, Braunschweig, Germany.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Zhang
authors.affiliation: Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, Beethovenstrasse 55, 38106, Braunschweig, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Ott
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, 61265, Brno, Czech Republic.|Department of Biophysics, Faculty of Science, Palacky University, Listopadu 12, 77146, Olomouc, Czech Republic.
authors.forename: Viktor
authors.initials: V
authors.lastname: Brabec
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, 61265, Brno, Czech Republic.|Department of Biophysics, Faculty of Science, Palacky University, Listopadu 12, 77146, Olomouc, Czech Republic.
authors.forename: Olga
authors.initials: O
authors.lastname: Stuchlikova
authors.affiliation: Research Centre for Integrated Analysis and Territorial Management, University of Bucharest, 1 Nicolae Balcescu bvd., District 1, 010055, Bucharest, Romania.
authors.forename: Ion C
authors.initials: IC
authors.lastname: Andronache
authors.affiliation: Institute of Translational Immunology, University Medical Center of the Johannes Gutenberg University, Langenbeckstrasse 1, 55131, Mainz, Germany.
authors.forename: Leonard
authors.initials: L
authors.lastname: Kaps
authors.affiliation: Institute of Translational Immunology, University Medical Center of the Johannes Gutenberg University, Langenbeckstrasse 1, 55131, Mainz, Germany.|Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA.
authors.forename: Detlef
authors.initials: D
authors.lastname: Schuppan
authors.affiliation: Organic Chemistry Laboratory, University Bayreuth, Universitätsstrasse 30, 95447, Bayreuth, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Schobert
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology*; D005296:Ferrous Compounds / Q000737:chemistry*; D006046:Gold / Q000737:chemistry / Q000494:pharmacology*; D000075163:Metallocenes / Q000737:chemistry*; D051379:Mice; D017382:Reactive Oxygen Species / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D005296:Ferrous Compounds; D000075163:Metallocenes; D017382:Reactive Oxygen Species; D006046:Gold; C004998:ferrocene
keywords: antitumor agents; antivascular activity; carbenes; gold; metal-based drugs