The antiproliferative properties of a series of structurally-related gold(I) and silver(I) linear complexes inspired to the clinically established gold-based drug auranofin were investigated in A2780 ovarian cancer cells and in their auranofin (A2780/AF-R) and cisplatin (A2780/CDDP-R) resistant counterparts. In A2780 cells and in the cisplatin-resistant subline, gold-based analogues manifested a cytotoxicity profile comparable or superior to auranofin, while the silver-based analogues were less active; both gold and silver complexes overcame cisplatin resistance. Yet, a high degree of cross resistance toward gold analogues was noticed in A2780/AF-R cells. In the same cell line cross-resistance for silver analogues was also observed, though lower. All metal complexes were scrutinized for their ability to inhibit thioredoxin reductase (TrxR), the putative primary target for AF: overall, gold compounds were more potent TrxR inhibitors than the corresponding silver compounds, probably, as the consequence of the stronger binding of gold to the active site selenocysteine residue. These results highlight that the thiosugar ligand of auranofin is not essential for cytotoxicity while the nature of the metal center (gold/silver) plays a relevant role in its modulation. In addition, a rather clear correlation was found between cytotoxic potency of tested compounds and their ability to inhibit TrxR activity, being gold compounds more effective than silver analogues. However, the residual TrxR activity, measured in A2780 cells treated with the half-maximal inhibitory concentrations of various metal complexes, resulted far higher than expected. These results suggest that additional cytotoxic mechanisms must be operative. The implications of these results are discussed.

在A2780卵巢癌细胞和其金诺芬（A2780 / AF-R）和顺铂（A2780 / CDDP-R）耐药性对应物。在A2780细胞和耐顺铂亚系中，基于金的类似物表现出的细胞毒性谱可与金诺芬媲美或优于金诺芬，而基于银的类似物活性较低。金和银的复合物都克服了顺铂的耐药性。然而，在A2780 / AF-R细胞中发现了对金类似物的高度交叉抗性。在相同的细胞系中，也观察到银类似物的交叉电阻，尽管较低。仔细检查所有金属配合物抑制硫氧还蛋白还原酶（TrxR）的能力，AF的主要目标：总体而言，金化合物比相应的银化合物更有效的TrxR抑制剂，这可能是由于金与活性位点硒代半胱氨酸残基的结合更强的结果。这些结果表明，金诺芬的硫糖配体对于细胞毒性不是必需的，而金属中心（金/银）的性质在其调节中起着重要的作用。此外，在被测化合物的细胞毒性效力与它们抑制TrxR活性的能力之间发现了相当明显的相关性，这是金化合物比银类似物更有效。但是，用各种金属配合物的半数最大抑制浓度处理过的A2780细胞中测得的残余TrxR活性远高于预期。这些结果表明，其他细胞毒性机制必须起作用。讨论了这些结果的含义。