Reactions of Auranofin and Its Pseudohalide Derivatives with Serum Albumin Investigated through ESI-Q-TOF MS

Pratesi, Alessandro; Cirri, Damiano; Ciofi, Lorenzo; Messori, Luigi

doi:10.1021/acs.inorgchem.8b02177

Cited by 46 publications

(64 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, we performed ESI-MS experiments also for AF and AF-I incubated with the two latter amino acids. Results confirmed the lack of reactivity for these two target molecules with AF and AF-I, further supporting the findings already published by some of us regarding the reactivity of auranofin and its derivatives toward protein targets (Landini et al, 2017;Pratesi et al, 2018;Zoppi et al, 2020).…”

Section: Esi Mass Spectrometrysupporting

confidence: 90%

“…Starting from our previous findings on the reactivity of AF and its analogs toward protein targets (Pratesi et al, 2014(Pratesi et al, , 2018Marzo et al, 2017Marzo et al, , 2019Cirri et al, 2019;Zoppi et al, 2020), here we have extended the investigation-at the molecular levelon the mode of action of these medicinally relevant gold(I) compounds. Specifically, we have focused our attention on AF and its analog where the thiosugar moiety is replaced by the iodide ligand.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, AF binds extensively and quickly to albumin. Accordingly, beyond albumin (Roberts et al, 1996;Pratesi et al, 2018), several non-genomic targets able to coordinate gold metal fragments have been hypothesized to be involved in determining its anticancer activity. Among them are the proteasome system (Micale et al, 2014), the NF-κB protein complex (Nakaya et al, 2011;, and thioredoxin reductase (TrxR) (Marzano et al, 2007;Pratesi et al, 2010Pratesi et al, , 2014Harbut et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Mechanistic Insights Into the Anticancer Properties of the Auranofin Analog Au(PEt3)I: A Theoretical and Experimental Study

et al. 2020

Self Cite

View full text Add to dashboard Cite

Au(PEt 3)I (AF-I hereafter), the iodide analog of the FDA-approved drug auranofin (AF hereafter), is a promising anticancer agent that produces its pharmacological effects through interaction with non-genomic targets such as the thioredoxin reductase system. AF-I is endowed with a very favorable biochemical profile showing potent in vitro cytotoxic activity against several cancer types including ovarian and colorectal cancer. Remarkably, in a recent publication, some of us reported that AF-I induces an almost complete and rapid remission in an orthotopic in vivo mouse model of ovarian cancer. The cytotoxic potency does not bring about highly severe side effects, making AF-I very well-tolerated even for higher doses, even more so than the pharmacologically active ones. All these promising features led us to expand our studies on the mechanistic aspects underlying the antitumor activity of AF-I. We report here on an integrated experimental and theoretical study on the reactivity of AF-I, in comparison with auranofin, toward relevant aminoacidic residues or their molecular models. Results point out that the replacement of the thiosugar moiety with iodide significantly affects the overall reactivity toward the amino acid residues histidine, cysteine, methionine, and selenocysteine. Altogether, the obtained results contribute to shed light into the enhanced antitumoral activity of AF-I compared with AF.

show abstract

Section: Esi Mass Spectrometrysupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Mechanistic Insights Into the Anticancer Properties of the Auranofin Analog Au(PEt3)I: A Theoretical and Experimental Study

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…These time course results demonstrate that AF is far more labile exchange inert than originally thought. [108]. Note that metal-free BSA consists of several post translational modifications (PTMs) and only the Cys34 with no PTM is able to coordinate directly to Au(I).…”

Section: Modifying the Phosphine And Thiosugar Ligands Of Auranofin Tmentioning

confidence: 99%

Evaluating Ligand Modifications of the Titanocene and Auranofin Moieties for the Development of More Potent Anticancer Drugs

et al. 2020

View full text Add to dashboard Cite

Over time platinum-based anticancer drugs have dominated the market, but their side effects significantly impact the quality of life of patients. Alternative treatments are being developed all over the world. The titanocene and auranofin families of compounds, discovered through an empirical search for other metal-based therapeutics, hold tremendous promise to improve the outcomes of cancer treatment. Herein we present a historical perspective of these compounds and review current efforts focused on the evolution of their ligands to improve their physiological solution stability, cancer selectivity, and antiproliferative performance, guided by a clear understanding of the coordination chemistry and aqueous speciation of the metal ions, of the cytotoxic mechanism of action of the compounds, and the external factors that limit their therapeutic potential. Newer members of these families of compounds and their combination in novel bimetallic complexes are the result of years of scientific research. We believe that this review can have a positive impact in the development and understanding of the metal-based drugs of gold, titanium, and beyond.

show abstract

“…This prompted investigators to analyze in detail the reactions of medicinal gold compounds with proteins. A systematic investigation on the interactions of the reference gold(I) drug auranofin with a series of model proteins, i.e., human serum albumin, carbonic anhydrase, superoxide dismutase, and hemoglobin, was recently carried out in our laboratory through mass spectrometry, and the resulting adducts could be characterized in molecular detail (Pratesi et al, 2016(Pratesi et al, , 2018(Pratesi et al, , 2019Magherini et al, 2018;Cirri et al, 2019;Zoppi et al, 2020). These studies revealed that auranofin targets quite selectively the free cysteine residues of proteins (Pratesi et al, 2018;Zoppi et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Reactions of Medicinal Gold(III) Compounds With Proteins and Peptides Explored by Electrospray Ionization Mass Spectrometry and Complementary Biophysical Methods

et al. 2020

Self Cite

View full text Add to dashboard Cite

Electrospray ionization mass spectrometry (ESI MS) is a powerful investigative tool to analyze the reactions of metallodrugs with proteins and peptides and characterize the resulting adducts. Here, we have applied this type of approach to four experimental anticancer gold(III) compounds for which extensive biological and mechanistic data had previously been gathered, namely, Auoxo6, Au 2 phen, AuL12, and Aubipyc. These gold(III) compounds were reacted with two representative proteins, i.e., human serum albumin (HSA) and human carbonic anhydrase I (hCA I), and with the C-terminal dodecapeptide of thioredoxin reductase. ESI MS analysis allowed us to elucidate the nature of the resulting metal-protein adducts from which the main features of the occurring metallodrug-protein reactions can be inferred. In selected cases, MS data were integrated and supported by independent 1 HNMR and UV-Vis absorption measurements to gain an overall description of the occurring processes. From data analysis, it emerges that most of the investigated gold(III) complexes, endowed with an appreciable oxidizing character, undergo quite facile reduction to gold(I); the resulting gold(I) species tightly associate with the above proteins/peptides with a remarkable selectivity for free cysteine residues. In contrast, in the case of the less-oxidizing Aubipyc complex, the gold(III) oxidation state is conserved, and a gold(III) fragment still containing the original ligand is found to be associated with the target proteins. It is notable that the C-terminal dodecapeptide of thioredoxin reductase containing the characteristic-Gly-Cys-Sec-Gly metal-binding motif is able in all cases to trigger gold(III)-to-gold(I) reduction. Our investigation allowed us to identify in detail the nature of the gold fragments that ultimately bind the protein targets and determine the exact binding stoichiometry; some insight on the reaction kinetics was also gained. Notably, a few clear correlations could be established between the structure of the metal complexes and the nature of the resulting protein adducts. The mechanistic implications of these findings are analyzed and thoroughly discussed. Overall, the present results set the stage to better understand the real target biomolecules of these gold compounds and elucidate at the atomic level their interaction modes with proteins and peptides.

show abstract

Reactions of Auranofin and Its Pseudohalide Derivatives with Serum Albumin Investigated through ESI-Q-TOF MS

Cited by 46 publications

References 34 publications

Mechanistic Insights Into the Anticancer Properties of the Auranofin Analog Au(PEt3)I: A Theoretical and Experimental Study

Mechanistic Insights Into the Anticancer Properties of the Auranofin Analog Au(PEt3)I: A Theoretical and Experimental Study

Evaluating Ligand Modifications of the Titanocene and Auranofin Moieties for the Development of More Potent Anticancer Drugs

Reactions of Medicinal Gold(III) Compounds With Proteins and Peptides Explored by Electrospray Ionization Mass Spectrometry and Complementary Biophysical Methods

Contact Info

Product

Resources

About