Structure-Activity Relationships of Silver(I)- and Gold(I)-NHC Complexes Reveal Distinctly Different Responses of Cisplatin-Resistant Ovarian Cancer to Bis-NHC-Gold(I) Derivatives
- Author(s)
- Julia H. Bormio Nunes, Christina Hacker, Monika Caban, Daniel Valcanover, Patrick A Yassemipour, Sebastian Türck, Ingo Ott, Lukas Skos, Andrea Bileck, Christopher Gerner, Samuel M Meier-Menches, Thomas Mohr, Walter Berger, Christian R Kowol, Petra Heffeter
- Abstract
Ovarian cancer (OC) is the most lethal gynecological malignancy, with platinum resistance posing a major therapeutic challenge. To explore alternatives, we synthesized silver- and gold-based N-heterocyclic carbene (NHC) complexes differing only in their central metal ion and evaluated their activity in platinum-resistant OC. Structure-activity relationships revealed distinct metal-dependent behaviors. Silver complexes showed little variation with ligand modifications, whereas gold complexes displayed pronounced differences. Two bis-NHC-gold compounds were of particular interest: In an isogenic OC resistance model (A2780 and A2780/cis), [(NHC2)2Au]Br showed cross-resistance, while [(NHC1)2Au]Br induced collateral sensitivity. These effects were independent of intracellular accumulation, apoptosis induction, or TrxR inhibition. Instead, proteomic and metabolic analyses demonstrated that [(NHC1)2Au]Br inhibited oxidative phosphorylation, forcing a metabolic shift to aerobic glycolysis. As A2780/cis cells already rely on maximal glycolysis, [(NHC1)2Au]Br caused an energy collapse. These findings highlight a metabolic vulnerability in cisplatin-resistant OC that may be exploited for the development of novel therapeutic candidates.
- Organisation(s)
- Department of Inorganic Chemistry, Department of Analytical Chemistry, Joint Metabolome Facility
- External organisation(s)
- Medizinische Universität Wien, Research Cluster Translational Cancer Therapy Research, Technische Universität Carolo-Wilhelmina zu Braunschweig
- Journal
- Journal of Medicinal Chemistry
- Volume
- 69
- Pages
- 2462-2480
- No. of pages
- 19
- ISSN
- 0022-2623
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c02355
- Publication date
- 01-2026
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 104003 Inorganic chemistry, 301305 Medical chemistry, 301206 Pharmacology, 301904 Cancer research
- ASJC Scopus subject areas
- Molecular Medicine, Drug Discovery
- Sustainable Development Goals
- SDG 3 - Good Health and Well-being
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/54ec97a7-627f-4038-ab5a-b71405c7316a