A dual approach to cancer treatment: gold(i) terpyridine derivatives as DNA binders and inhibitors of mammalian thioredoxin reductase†

Abstract

Gold(I) complexes featuring a phosphine-substituted terpyridine (4′-PPh₂terpy), along with various ancillary ligands, have been successfully synthesised. All derivatives, characterised by the general formula [Au(L)(4′-PPh₂terpy)] (where L represents phosphine, chloride, alkynyl, or thiolate), exhibit remarkable activity against diverse tumour cell lines, including HT-29, MCF-7, and MDA-MB-231, with particularly noteworthy efficacy against the triple negative breast cancer MDA-MB-231 cell line. Notably, all complexes demonstrate superior efficacy compared to the reference auranofin, showcasing IC₅₀ values ten-fold lower. Additionally, they exhibit a certain level of selectivity towards healthy cells (primary fibroblasts). The ability of different ancillary ligands to undergo ligand exchange reactions with thiol groups, such as NAC, has been assessed via NMR. A correlation between the leaving group capacities of various ligands and the speed of ligand exchange reactions has been observed, following this order: alkynyl < phosphine < thiolate < chloride. Moreover, efforts were made to elucidate potential biological targets and the underlying mechanism of action through which these Au(I) compounds impede cell proliferation. Flow cytometry measurements have indicated several cellular responses, including apoptotic cell death, cell cycle arrest in the G0/G1 phase, increased ROS production, and a decrease in mitochondrial membrane potential (ΔΨ). DNA binding studies revealed that the selected derivatives interact with DNA by intercalation. Additionally, investigations on the inhibition of the TrxR system yielded compelling findings. The Au(I) complexes exhibited potent enzyme inhibition, albeit variations were noted based on the ancillary ligand employed. A clear correlation emerged between the inhibition observed and the capability to displace the ancillary ligand with the selenol moieties of TrxR (the effectiveness follows the same order as observed in the study of ligand exchange reactions). Notably, the chloride ligand yielded the most promising results, demonstrating inhibition levels comparable to auranofin, one of the foremost TrxR inhibitors. This suggests a dual approach for cancer therapy with complexes targeting two key biological targets.