Multifunctional auranofin analogues: dual-targeting TSPO/TrxR gold(I) complexes with activity in resistant ovarian cancer

Auranofin (AF) is a clinically approved gold(I) complex used for the treatment of rheumatoid arthritis and currently under investigation for drug repurposing in oncology. Its anticancer activity has been mainly associated with the inhibition of thioredoxin reductase (TrxR), an enzyme crucial for the maintenance of the redox balance of cell. Accordingly, this triggered intense research in the development of novel AF-analogues. Herein, a new series of AF-inspired gold(I) complexes (1–4) was designed and synthesized by replacing the thiosugar moiety with ligands targeting the translocator protein (TSPO), a mitochondrial protein overexpressed in several cancers, including ovarian cancer. The new complexes showed strong TrxR inhibition and sub/low-nanomolar TSPO affinity. All compounds exhibited low-micromolar cytotoxicity in ovarian cancer cells, including cisplatin- and AF-resistant variants, with a milder reduction in activity than AF and cisplatin in resistant models. Computational studies indicated that replacement of the thiosugar moiety with TSPO ligands affects the stability of the Au–S and Au–P bonds, leading to a different activation mode compared with AF. In parallel, ICP-AES analysis revealed comparable intracellular gold accumulation for complexes 1–4 and AF, indicating that differences in biological activity are not mainly driven by cellular uptake, but rather by distinct intracellular processing and target engagement. Overall, these findings support the conjugation of the [Au(PEt3)]+ fragment with mitochondria-targeting ligands as a promising strategy for developing multifunctional Au-based complexes.