Structure-activity relationships in a series of auranofin analogues showing remarkable antiproliferative properties.

Abstract

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 auranofin: 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.

• Authors: Ida Landini, Lara Massai, Damiano Cirri, Tania Gamberi, Paolo Paoli, Luigi Messori, Enrico Mini, Stefania Nobili
• Journal: Journal of inorganic biochemistry (J Inorg Biochem) Vol. 208 Pg. 111079 (07 2020) ISSN: 1873-3344 [Electronic] United States
• PMID: 32497830 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Neoplasm Proteins
• Auranofin
• Thioredoxin-Disulfide Reductase

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Auranofin (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Female
• Humans
• Neoplasm Proteins (antagonists & inhibitors, metabolism)
• Ovarian Neoplasms (drug therapy, enzymology, pathology)
• Structure-Activity Relationship
• Thioredoxin-Disulfide Reductase (antagonists & inhibitors, metabolism)