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Ferrocenyl‐Coupled N‐Heterocyclic Carbene Complexes of Gold(I): A Successful Approach to Multinuclear Anticancer Drugs |
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| Authors: | Dr. Julienne K. Muenzner Dr. Bernhard Biersack Alexander Albrecht Tobias Rehm Dr. Ulrike Lacher Dr. Wolfgang Milius Prof. Dr. Angela Casini Dr. Jing‐Jing Zhang Prof. Dr. Ingo Ott Prof. Dr. Viktor Brabec Olga Stuchlikova Dr. Ion C. Andronache Leonard Kaps Prof. Dr. Dr. Detlef Schuppan Prof. Dr. Rainer Schobert |
| Affiliation: | 1. Organic Chemistry Laboratory, University Bayreuth, Bayreuth, Germany;2. Lehrstuhl für Anorganische Chemie I, Universit?t Bayreuth, Bayreuth, Germany;3. Department of Pharmacokinetics, Toxicology, and Targeting, University of Groningen, Groningen, The Netherlands;4. School of Chemistry, Cardiff University, Main Building, Cardiff, UK;5. Medicinal and Pharmaceutical Chemistry, Technische Universit?t Braunschweig, Braunschweig, Germany;6. Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno, Czech Republic;7. Department of Biophysics, Faculty of Science, Palacky University, Olomouc, Czech Republic;8. Research Centre for Integrated Analysis and Territorial Management, University of Bucharest, Bucharest, Romania;9. Institute of Translational Immunology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany;10. Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA |
| 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 %. |
| Keywords: | antitumor agents antivascular activity carbenes gold metal-based drugs |