# 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

## TL;DR

This study explores how silver and gold-based compounds affect platinum-resistant ovarian cancer, finding that a specific gold compound targets cancer cell metabolism.

## Contribution

The study identifies a gold-based compound that exploits metabolic vulnerabilities in cisplatin-resistant ovarian cancer cells.

## Key findings

- Silver complexes showed minimal variation in activity with ligand modifications.
- The bis-NHC–gold compound [(NHC1)2Au]Br caused energy collapse in cisplatin-resistant cells by inhibiting oxidative phosphorylation.
- The effects of [(NHC1)2Au]Br were independent of apoptosis or TrxR inhibition, highlighting a novel metabolic mechanism.

## 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.