Reaction of Zn7Metallothionein with cis- and trans-[Pt(N-donor)2Cl2] Anticancer Complexes:  trans-PtII Complexes Retain Their N-Donor Ligands

Knipp, Markus; Karotki, Andrei V.; Chesnov, Serge; Natile, Giovanni; Sadler, Peter J.; Brabec, Viktor; Vašák, Milan

doi:10.1021/jm070271l

Cited by 85 publications

(107 citation statements)

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“…[265] Vasak et al reported on comparative studies of cis-and trans-based platinum complexes towards both Zn 7 MT-2 and Zn 7 -MT-3 using mass spectrometry amongst other techniques. [120,264] The difference between those two MTs is that the biosynthesis and expression of MT-2 are triggered by metal ions (amongst other compounds), whereas MT3 is not inducible. [120] In the case of MT-2, results showed that trans-platinum complexes react faster than the cis-ones.…”

Section: Metallothioneinsmentioning

confidence: 99%

“…[120,264] The difference between those two MTs is that the biosynthesis and expression of MT-2 are triggered by metal ions (amongst other compounds), whereas MT3 is not inducible. [120] In the case of MT-2, results showed that trans-platinum complexes react faster than the cis-ones. Characterization of the adducts revealed that in the case of the cis-Pt(II) compounds, all initial ligands were replaced by cysteine residues, whereas trans-Pt(II) complexes were found to retain their N-donor ligands, thus remaining in a potentially biologically active form.…”

Section: Metallothioneinsmentioning

confidence: 99%

“…Characterization of the adducts revealed that in the case of the cis-Pt(II) compounds, all initial ligands were replaced by cysteine residues, whereas trans-Pt(II) complexes were found to retain their N-donor ligands, thus remaining in a potentially biologically active form. [120] The steric hindrance of the ligands as well as the electrophilicity of the platinum centre were also pointed out as influencing the kinetics of the reactivity of replacement of the zinc ions by platinum. [120] Using MT-3, a similar trend was reported, transplatin reacting faster than cisplatin, and confirmation of the release of a stoichiometric amount of Zn from the peptide upon Pt binding was shown.…”

Section: Metallothioneinsmentioning

confidence: 99%

“…[120] The steric hindrance of the ligands as well as the electrophilicity of the platinum centre were also pointed out as influencing the kinetics of the reactivity of replacement of the zinc ions by platinum. [120] Using MT-3, a similar trend was reported, transplatin reacting faster than cisplatin, and confirmation of the release of a stoichiometric amount of Zn from the peptide upon Pt binding was shown. [264] As in the case of MT-2, transplatin was shown to retain its ammonia ligands, while cisplatin lost all of its initial ligands, replaced by cysteine thiolates.…”

Section: Metallothioneinsmentioning

confidence: 99%

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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

105

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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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Section: Metallothioneinsmentioning

confidence: 99%

Section: Metallothioneinsmentioning

confidence: 99%

Section: Metallothioneinsmentioning

confidence: 99%

Section: Metallothioneinsmentioning

confidence: 99%

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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

105

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“…The merged band changed from orange to red after 4 h (Figure 3I), suggesting platination of FAM-G15. Therefore, an interesting effect of citrate is to increase the selectivity of cisplatin towards guanine compared to adenine, 15 which might have implications for guanine being the eventual target of cisplatin. [37][38][39] In summary, we employed fluorescently-labeled oligonucleotides for studying the reaction between cisplatin and DNA.…”

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confidence: 99%

Citrate inhibition of cisplatin reaction with DNA studied using fluorescently labeled oligonucleotides: implication for selectivity towards guanine

2013

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The reaction between cisplatin and DNA is conveniently studied using fluorescently labeled oligonucleotides and gel electrophoresis; as an example of application, the inhibition of this reaction by citrate is demonstrated, which might 10 increase selectivity of cisplatin towards guanine over adenine.Cisplatin is one of the most successful and important anticancer drugs. [1][2][3][4] It is generally accepted that DNA is the molecular target of cisplatin, forming intrastrand crosslinked guanines, 1 although the exact mechanism is still under 15 debate. 5 A lot has already been learned about the reaction between DNA and cisplatin. 6 The difference in the Clconcentration outside a cell (~100 mM) and inside (~4-12 mM) might facilitate dissociation of Cl -and adding water inside the cell. 1 The aquated product is trapped in the cell to 20 react with various nucleophilic species including DNA. 7,8 Mechanisms related to electron transfer have also been proposed. 9 Due to the lack of appropriate analytical tools to follow cisplatin inside live cells, 5 most studies were carried out in simple buffers. The cellular environment, however, is 25 much more complex containing numerous small molecules, nucleic acids and proteins that compete for cisplatin binding. 10,11 The cisplatin concentration inside cells is estimated to be just nanomolar to low micromolar. 5 Many cellular compounds can tightly bind to cisplatin, leaving little 30 free cisplatin for DNA binding. Examples of such competitors include sulfer containing proteins, 12,13 glutathione (GSH), 14,15 and even inorganic anions. 16 Before cisplatin can react with DNA, it has to be released from these competing ligands. 17 Many an initial test, we employed FAM-labeled 15-mer DNA homopolymers. The DNAs were mixed with increasing concentrations of cisplain for 16 h and the samples were then loaded into a non-denaturing polyacrylamide gel. A gradual shift of the FAM-A15 band with reduced mobility was 70 observed with increasing cisplatin concentration ( Figure 1A), suggesting reaction between this DNA and cisplatin. The Pt-DNA adduct did not migrate as a single band, suggesting the presence of a broad range of products, possibly due to different levels and positions of platination. Fluorescence 75 quenching was also observed, especially at high Pt concentrations. On the other hand, no shift was observed with FAM-T15 and its fluorescence just dropped in intensity with increasing cisplatin concentration ( Figure 1B). Reactions also occurred with FAM-C15 and its product distribution pattern 80 was quite different, where discrete bands were observed at low Pt concentrations and the gel smeared at high Pt concentrations ( Figure 1C). Finally, FAM-G15 showed slightly smeared gel even for the initial free DNA, possibly due to its tendency to form various secondary structures such as inter- 85 and intra-molecular quadruplexes ( Figure 1D). Mass spectrum of FAM-G15 showed a few high molecular weight species, consistent with the smeared gel ( Figure S1, ESI). Addition of cispla...

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Metallo‐Drugs and Their Action

Dabrowiak

2009

Metals in Medicine

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Introduction of metallo-drugs into the body exposes them to reaction with many substances in the biological system. While the main targets for these agents are proteins and DNA, passage through the blood and eventually into the cell allows the metal complex to come in contact which substances that can modify its composition. The main focus of this chapter is on giving a brief overview of the structures of proteins and DNA and summarizing the ways in which these important biomolecules react with metal ions. Since many metalcontaining agents used in medicine have easily-displaced ligands, the manner in which complexes react with simple ions found in the blood and cells will also be presented and discussed. In addition to highlighting the biological chemistry of metallo-drugs, it is also important to outline how their pharmacological effects are measured and, since there is increasing demand for more effective agents, how a discovery made in the laboratory makes its way through the approval process to become a drug. Proteins as targets for metallo-drugsThe human body has tens of thousands of different proteins, involved in a variety of different catalytic, transport and structural roles. If a metal ion introduced into the body in the form of a metallo-drug attaches itself to a part of the protein that is critical for function, the ability of the protein to perform its biological task could be impaired, which could be enough to kill the cell. For example, many catalytically-active proteins called metallo-enzymes have naturally-occurring metal ions such as Zn þ2 or Cu þ1/þ2 in their active sites. Since the same ligands on the protein that bind to the naturally-occurring metal ion could also serve as donor atoms to the metal ion in a metallo-drug, addition of the drug to the protein could result in displacement of the natural metal ion, causing the enzyme to be catalytically inactive. Many proteins in the body use metal ions as a means of organizing their structure. Since some of these metallo-proteins are involved in gene expression and interact directly with DNA, disruption of their structure by substituting the natural metal ion with one supplied by a metallo-drug could affect the specificity and affinity of the interaction, thus influencing the ability of the cell to make the proper proteins for survival. Metals in MedicineJames C. DabrowiakStructurally, proteins are long polyamide polymers that are made up of monomer units called amino acids, the structures of which, along with their three-and one-letter amino acid codes, are shown in Figure 2.1. As is evident in the figure, all of the amino acids have an amino, a carboxylic acid and a hydrogen atom attached to the a-carbon atom of the compound, but the forth group on the a-carbon, called the side chain, characterizes each amino acid. Except for glycine, all of the common amino acids have four different groups attached to the a-carbon atom, which makes the atom, and thus the amino acid, chiral. With the exception of cysteine, which has the R absolute configuration...

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Reaction of Zn₇Metallothionein with cis- and trans-[Pt(N-donor)₂Cl₂] Anticancer Complexes: trans-Pt^II Complexes Retain Their N-Donor Ligands

Cited by 85 publications

References 61 publications

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

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

Citrate inhibition of cisplatin reaction with DNA studied using fluorescently labeled oligonucleotides: implication for selectivity towards guanine

Metallo‐Drugs and Their Action

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