Synthesis and anticancer properties of gold (I) N-Heterocyclic Carbene complexes bearing peptidic groups

While platinum-based compounds remain the cornerstone of metallodrugs in oncology, their clinical application is often hindered by severe side effects. This has motivated the exploration of alternative metal-based therapies, among which gold compounds have emerged as a promising alternative due to their distinct mechanisms of action, often targeting proteins like thioredoxin reductase (TrxR) rather than DNA. Gold(I) complexes bearing N-heterocyclic carbene (NHC) ligands are particularly noteworthy for their enhanced stability. Furthermore, the incorporation of amino acids into drug design can improve aqueous solubility, bioavailability, biocompatibility and tumor selectivity, reducing overall toxicity. This work details the synthesis and biological evaluation of a series of amino acid-functionalized gold(I)–NHC complexes. A novel imidazolium salt (proligand) was successfully synthesized, characterized, and designed by linking an NHC motif to a methylated proline ester via an aromatic linker. Using this precursor, five new gold(I) complexes featuring diverse auxiliary ligands, a chloride (Complex 1), a thiolate (Complex 2), a homobiscarbene (Complex 3), a phosphine (Complex 4), and a heterobiscarbene (Complex 5) were obtained, purified, and fully characterized. The stability of the synthesized compounds in solution was assessed by UV-visible spectroscopy founding that all synthesized compounds were stable in PBS for at least 48 hours. Interaction with DNA was also evaluated and all complexes were identified as moderate-to-strong DNA intercalators. Finally, in vitro cytotoxicity of all the developed compounds was assessed via the MTT assays, revealing that complexes 4 and 5 are highly promising anticancer candidates. Both complexes exhibited superior antitumoral efficacy, with IC50 values lower than the established reference drugs, auranofin and cisplatin. These results demonstrate the strong potential of NHC-aminoacid functionalized gold(I) complexes as scaffolds for the development of novel antitumor agents.