Quantification of bindings of organometallic ruthenium complexes to GSTπ by mass spectrometry

Lin, Yu; Huang, Yongdong; Zheng, Wei; Wu, Kui; Luo, Qun; Zhao, Yao; Xiong, Shaoxiang; Wang, Fuyi

doi:10.1016/j.jinorgbio.2015.02.015

Cited by 10 publications

(12 citation statements)

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“…The inhibition of GSTs by ruthenium compounds is already well established . Furthermore, more recently, and now 66 years after the first report by Dwyer and Gyarfas in 1952, ruthenium‐based complexes have been rediscovered as potential anti‐cholinesterase agents with interesting pharmaceutical potential …”

Section: Introductionmentioning

confidence: 99%

Organoruthenium Prodrugs as a New Class of Cholinesterase and Glutathione‐S‐Transferase Inhibitors

et al. 2018

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A small library of 17 organoruthenium compounds with the general formula [Ru (fcl)(chel)(L)] (in which fcl=face capping ligand, chel=chelating bidentate ligand, and L=monodentate ligand) were screened for inhibitory activity against cholinesterases and glutathione-S-transferases of human and animal origins. Compounds were selected to include different chelating ligands (i.e., N,N-, N,O-, O,O-, S,O-) and monodentate ligands that can modulate the aquation rate of the metal species. Compounds with a labile ruthenium chloride bond that provided rapid aquation were found to inhibit both sets of enzymes in reversible competitive modes and at pharmaceutically relevant concentrations. When applied at concentrations that completely abolish the activity of human acetylcholinesterase, the lead compound [(η -p-cymene)Ru(pyrithionato)Cl] (C1 a) showed no undesirable physiological responses on the neuromuscular system. Finally, C1 a was not cytotoxic against non-transformed cells at pharmaceutically relevant concentrations.

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Section: Introductionmentioning

confidence: 99%

Organoruthenium Prodrugs as a New Class of Cholinesterase and Glutathione‐S‐Transferase Inhibitors

et al. 2018

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“…Recently, our group reported a quantitative MS method for determination of the ratio of ruthenium complex‐bound peptides with a specific isotopic labelling strategy to amine groups of peptides using NAS . This method was successful in determining the binding ratio of ruthenium anticancer complexes to Cys15, Cys48, Met92 and Cys102 in GST‐π.…”

Section: Discussionmentioning

confidence: 99%

“…This method was successful in determining the binding ratio of ruthenium anticancer complexes to Cys15, Cys48, Met92 and Cys102 in GST‐π. However, when the NAS isotopic labelling occurred only at the N‐terminal, the mass difference between light and heavy peptides was only 3 Da, where the isotopic signals may overlap, so a correction based on the isotopic ratios of the peptide pair was required for accurate quantification . Moreover, as the NAS labelling is applied to terminal amines and amines of lysine in the side chain, the primary MS‐based quantification cannot distinguish the exact binding sites at the single residue level if there is more than one binding site in a metallated peptide.…”

Section: Discussionmentioning

confidence: 99%

“…For example, cisplatin binds to methionine, histidine, cysteine, lysine, glutamine, etc., residues of a variety of proteins, leading to protein dysfunction. For ruthenium anticancer complexes, the frequent coordination sites on proteins are the thiol/thioester of cysteine/methionine and the imidazole of histidine . As thiols usually play many vital roles in the functions of proteins, the mapping of thiol‐binding sites and the quantification of the binding ratio of metal complexes to each site are of great importance.…”

Section: Introductionmentioning

confidence: 99%

“…A trivalent arsenic species has been applied as both labelling and reporter group in a tandem MS study to evaluate the activity of cysteines in a protein . In recent years, we have reported a bottom‐up MS method to identify the binding sites of ruthenium complexes in human glutathione‐S‐transferase‐π (GST‐π), and determined the ratio of the ruthenated peptides with a specific isotopic labelling strategy for the amine groups of peptides by N ‐acetoxysuccinimide (NAS) . However, when this labelling reagent reacts only with the terminal amine, a mass difference of only 3 Da is generated between the light and heavy peptides.…”

Section: Introductionmentioning

confidence: 99%

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Mass spectrometric quantification of the binding ratio of metal‐based anticancer complexes with protein thiols

Han

Guo

Zheng

et al. 2019

Rapid Comm Mass Spectrometry

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Rationale The binding ratio of metal complexes with cysteinyl thiols in proteins plays an important role in deciphering the mechanisms of action of therapeutic metal complexes, but its analysis is still a significant challenge. In this work, a quantitative mass spectrometry method is developed to determine the binding ratio of metal‐based anticancer complexes with cysteines in human copper chaperone protein Atox1. Methods A novel strategy based on a thiol‐specific stable isotopic labelling reagent was developed to determine the binding ratio of metal‐based anticancer complexes, namely cisplatin and organometallic ruthenium complex [(η6‐biphenyl)RuCl(en)]PF6 (en = ethylenediamine), with the cysteinyl residues of Atox1. Results Both cisplatin and the ruthenium complex were reactive not only to Cys15 and/or Cys18, the copper(I) binding site of Atox1, but also to Cys44. The binding ratios of the ruthenium complex with the cysteinyl residues were much higher than those of cisplatin. However, the addition of copper(I) could markedly increase the binding ratios of cysteinyl residues of Atox1 with cisplatin, but not with the ruthenium complex. Conclusions This strategy can not only precisely determine the binding ratios of metal complexes to protein thiols, but also be helpful in distinguishing thiol‐binding sites from other binding sites of metal complexes in proteins. We expect wide application of this method to the research of covalent/coordinative interactions between metal complexes and protein thiols.

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Mass spectrometry as a powerful tool to study therapeutic metallodrugs speciation mechanisms: Current frontiers and perspectives

Wenzel

Casini

2017

Coordination Chemistry Reviews

108

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Metal-based compounds form a promising class of therapeutic agents, whose mechanisms of action still need to be elucidated, and that are in general prone to undergo extensive speciation in physiological environment. Thus, determination of the fate of the metal compounds in complex biological systems, contributing to their overall pharmacological and toxicological profiles, is important to develop more rationalised and targeted metal-based drugs. To these aims, a number of spectroscopic and biophysical methods, as well as analytical techniques, are nowadays extensively applied to study the reactivity of metal complexes with different biomolecules (e.g. nucleic acids, proteins, buffer components). Among the various techniques, molecular mass spectrometry (MS) has emerged in the last decade as a major tool to characterise the interactions of metallodrugs at a molecular level. In this review, we present an overview of the information available on the reactivity of various families of therapeutic metallodrugs (mainly anticancer compounds based on Pt, Ru, Au and As) with biomolecules studied by different MS techniques, including high-resolution ESI-, MALDI-and ion mobility-MS among others. Representative examples on the potential of the MS approach to study non-covalent interactions are also discussed. The review is organized to present results obtained on samples with different degrees of complexity, from the interactions of metal compounds with small model nucleophiles (amino acids and nucleobases), model peptides/oligonucleotides, target proteins/nucleic acids, to the analysis of serum, cell extracts and tissue samples. The latter requiring combination of proteomic methods with advanced MS techniques. Correlations between molecular reactivity of metallodrugs and biological activity are hard to establish, but differences in the reactivity of metallodrugs to biomolecules and their different adducts, as revealed by MS methods, may indicate differences in their modes of action. Overall, the knowledge offered by MS methods on metallodrugs speciation is invaluable to establish new rules and define new trends in the periodic table aimed at rationalizing the behavior of metal compounds in complex living systems. Keywordsmetal-based drugs; proteins; nucleic acids; mass spectrometry; metallomics. Corresponding Author Angela Casini Corresponding Author's InstitutionCardiff University To view all the submission files, including those not included in the PDF, click on the manuscript title on your EVISE Homepage, then click 'Download zip file'. Order of Authors 1 Answers to Reviewers Reviewer 1 The authors have made some effort to answer suggestions and the manuscript is improved. Since it is a review, there is, strictly, no new information but nevertheless the compilation of data and references could be useful.Answer: no further comments. Liu et al." in place of "Lu et al." iv) Some symbols in the PDF file are not correctly displayed. Reviewer Answer:We have inserted all the minor modifications requested by this rev...

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Quantification of bindings of organometallic ruthenium complexes to GSTπ by mass spectrometry

Cited by 10 publications

References 37 publications

Organoruthenium Prodrugs as a New Class of Cholinesterase and Glutathione‐S‐Transferase Inhibitors

Organoruthenium Prodrugs as a New Class of Cholinesterase and Glutathione‐S‐Transferase Inhibitors

Mass spectrometric quantification of the binding ratio of metal‐based anticancer complexes with protein thiols

Mass spectrometry as a powerful tool to study therapeutic metallodrugs speciation mechanisms: Current frontiers and perspectives

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