Synthesis, chemical characterization, and biological evaluation of a novel auranofin derivative as an anticancer agent

Cirri, Damiano; Massai, Lara; Giacomelli, Chiara; Trincavelli, Maria Letizia; Guerri, Annalisa; Gabbiani, Chiara; Messori, Luigi; Pratesi, Alessandro

doi:10.1039/d2dt00836j

Cited by 11 publications

(7 citation statements)

References 68 publications

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“…Notably, adducts are formed with all gold compounds although in different abundances. The nature of the protein bound gold fragments is specified in the spectra [21,45,46]. lodrug derivatives.…”

Section: Hsamentioning

confidence: 99%

Protein Metalation by Medicinal Gold Compounds: Identification of the Main Features of the Metalation Process through ESI MS Experiments

2023

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Gold compounds form a new class of promising anticancer agents with innovative modes of action. It is generally believed that anticancer gold compounds, at variance with clinically established platinum drugs, preferentially target proteins rather than nucleic acids. The reactions of several gold compounds with a few model proteins have been systematically explored in recent years through ESI MS measurements to reveal adduct formation and identify the main features of those reactions. Here, we focus our attention on a group of five gold compounds of remarkable medicinal interest, i.e., Auranofin, Au(NHC)Cl, [Au(NHC)2]PF6, Aubipyc, and Auoxo6, and on their reactions with four different biomolecular targets, i.e., the proteins HEWL, hCA I, HSA and the C-terminal dodecapeptide of the enzyme thioredoxin reductase. Complete ESI MS data are available for those reactions due to previous experimental work conducted in our laboratory. From the comparative analysis of the ESI MS reaction profiles, some characteristic trends in the metallodrug-protein reactivity may be identified as detailed below. The main features are described and analyzed in this review. Overall, all these observations are broadly consistent with the concept that cytotoxic gold drugs preferentially target cancer cell proteins, with a remarkable selectivity for the cysteine and selenocysteine proteome. These interactions typically result in severe damage to cancer cell metabolism and profound alterations in the redox state, leading to eventual cancer cell death.

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Section: Hsamentioning

confidence: 99%

Protein Metalation by Medicinal Gold Compounds: Identification of the Main Features of the Metalation Process through ESI MS Experiments

2023

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“…Both selected biomolecules contain a free cysteine residue which is, according to several published papers, a preferential binding site for gold(I) complexes due to the high affinity of gold(I) for amino acids residues bearing sulfur atoms [ 12 , 13 , 14 ]. Thus, the interactions between all study compounds and the mentioned proteins were investigated through ESI-MS experiments according to a well-established experimental protocol [ 4 , 15 ]; indeed, in the recent literature, several studies characterizing the formation of adducts between a variety of model proteins and many metal-based drugs have been reported [ 16 , 17 ]. The recorded ESI mass spectra highlight that all gold compounds act as prodrugs by binding the proteins through a metal fragment, which is the “active part” of the compound itself ( Figure 3 and Figure 4 ).…”

Section: Resultsmentioning

confidence: 99%

“…Accordingly, several efforts have been conducted to make small and systematic chemical modifications to the AF scaffold, with the aim of improving its anticancer properties. Many modification attempts were described so far, such as the preparation of derivatives in which the thiosugar ligand is replaced by halide ligands [3] or other biologically active molecules [4]. Another relevant modification was reported by F. Shaw who replaced the sulfur of the thiosugar ligand with a selenium atom, affording the so-called selenoauranofin [5]; other studies explored the effects of a variety of modifications in the phosphine ligand [6,7].…”

Section: Introductionmentioning

confidence: 99%

Chemical Modification of Auranofin Yields a New Family of Anticancer Drug Candidates: The Gold(I) Phosphite Analogues

et al. 2023

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A panel of four novel gold(I) complexes, inspired by the clinically established gold drug auranofin (1-Thio-β-D-glucopyranosatotriethylphosphine gold-2,3,4,6-tetraacetate), was prepared and characterized. All these compounds feature the replacement of the triethylphosphine ligand of the parent compound auranofin with a trimethylphosphite ligand. The linear coordination around the gold(I) center is completed by Cl−, Br−, I− or by the thioglucose tetraacetate ligand (SAtg). The in-solution behavior of these gold compounds as well as their interactions with some representative model proteins were comparatively analyzed through 31PNMR and ESI-MS measurements. Notably, all panel compounds turned out to be stable in aqueous media, but significant differences with respect to auranofin were disclosed in their interactions with a few leading proteins. In addition, the cytotoxic effects produced by the panel compounds toward A2780, A2780R and SKOV-3 ovarian cancer cells were quantitated and found to be in the low micromolar range, since the IC50 of all compounds was found to be between 1 μM and 10 μM. Notably, these novel gold complexes showed large and similar inhibition capabilities towards the key enzyme thioredoxin reductase, again comparable to those of auranofin. The implications of these results for the discovery of new and effective gold-based anticancer agents are discussed.

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“…The free and DOTA-NHS-ester conjugated protein were further characterized through ESI MS analysis according to standard procedures. , The ESI MS spectrum of the free protein is shown in Figure a. The deconvoluted ESI MS spectrum shows an intense and very well resolved single peak with a mass of 34 599 Da.…”

Section: Resultsmentioning

confidence: 99%

Large Protein Assemblies for High-Relaxivity Contrast Agents: The Case of Gadolinium-Labeled Asparaginase

et al. 2022

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Biologics are emerging as the most important class of drugs and are used to treat a large variety of pathologies. Most of biologics are proteins administered in large amounts, either by intramuscular injection or by intravenous infusion. Asparaginase is a large tetrameric protein assembly, currently used against acute lymphoblastic leukemia. Here, a gadolinium(III)-DOTA derivative has been conjugated to asparaginase, and its relaxation properties have been investigated to assess its efficiency as a possible theranostic agent. The field-dependent 1 H longitudinal relaxation measurements of water solutions of gadolinium(III)-labeled asparaginase indicate a very large increase in the relaxivity of this paramagnetic protein complex with respect to small gadolinium chelates, opening up the possibility of its use as an MRI contrast agent.

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Synthesis, chemical characterization, and biological evaluation of a novel auranofin derivative as an anticancer agent

Abstract: A novel gold(I) complex inspired by the known medicinal inorganic compounds auranofin and thimerosal, namely ethylthiosalicylate(triethylphosphine)gold(I) (AFETT hereafter), was synthesized and characterised and its structure solved through X-ray diffraction. The...

Cited by 11 publications

References 68 publications

Protein Metalation by Medicinal Gold Compounds: Identification of the Main Features of the Metalation Process through ESI MS Experiments

Protein Metalation by Medicinal Gold Compounds: Identification of the Main Features of the Metalation Process through ESI MS Experiments

Chemical Modification of Auranofin Yields a New Family of Anticancer Drug Candidates: The Gold(I) Phosphite Analogues

Large Protein Assemblies for High-Relaxivity Contrast Agents: The Case of Gadolinium-Labeled Asparaginase

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