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Structure-activity relationships in a series of auranofin analogues showing remarkable antiproliferative properties.
J Inorg Biochem. 2020 Jul; 208:111079.JI

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+Show Affiliations

Department of Health Sciences, University of Florence, Florence, Italy.Department of Chemistry "Ugo Schiff", University of Florence, Florence, Italy.Department of Chemistry "Ugo Schiff", University of Florence, Florence, Italy.Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.Department of Chemistry "Ugo Schiff", University of Florence, Florence, Italy. Electronic address: luigi.messori@unifi.it.Department of Health Sciences, University of Florence, Florence, Italy. Electronic address: enrico.mini@unifi.it.Department of Health Sciences, University of Florence, Florence, Italy.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32497830

Citation

Landini, Ida, et al. "Structure-activity Relationships in a Series of Auranofin Analogues Showing Remarkable Antiproliferative Properties." Journal of Inorganic Biochemistry, vol. 208, 2020, p. 111079.
Landini I, Massai L, Cirri D, et al. Structure-activity relationships in a series of auranofin analogues showing remarkable antiproliferative properties. J Inorg Biochem. 2020;208:111079.
Landini, I., Massai, L., Cirri, D., Gamberi, T., Paoli, P., Messori, L., Mini, E., & Nobili, S. (2020). Structure-activity relationships in a series of auranofin analogues showing remarkable antiproliferative properties. Journal of Inorganic Biochemistry, 208, 111079. https://doi.org/10.1016/j.jinorgbio.2020.111079
Landini I, et al. Structure-activity Relationships in a Series of Auranofin Analogues Showing Remarkable Antiproliferative Properties. J Inorg Biochem. 2020;208:111079. PubMed PMID: 32497830.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structure-activity relationships in a series of auranofin analogues showing remarkable antiproliferative properties. AU - Landini,Ida, AU - Massai,Lara, AU - Cirri,Damiano, AU - Gamberi,Tania, AU - Paoli,Paolo, AU - Messori,Luigi, AU - Mini,Enrico, AU - Nobili,Stefania, Y1 - 2020/03/28/ PY - 2020/01/03/received PY - 2020/03/08/revised PY - 2020/03/22/accepted PY - 2020/6/5/pubmed PY - 2020/6/5/medline PY - 2020/6/5/entrez KW - Auranofin analogues KW - Gold(I) compounds KW - In vitro tumor models KW - Silver(I) compounds KW - Thioredoxin reductase SP - 111079 EP - 111079 JF - Journal of inorganic biochemistry JO - J. Inorg. Biochem. VL - 208 N2 - 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. SN - 1873-3344 UR - https://www.unboundmedicine.com/medline/citation/32497830/Structure-activity_relationships_in_a_series_of_auranofin_analogues_showing_remarkable_antiproliferative_properties L2 - https://linkinghub.elsevier.com/retrieve/pii/S0162-0134(20)30107-0 DB - PRIME DP - Unbound Medicine ER -
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