Metal-based antitumour drugs in the post genomic era

Dyson, Paul J.; Sava, Gianni

doi:10.1039/b601840h

Cited by 737 publications

(543 citation statements)

References 39 publications

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“…Additionally, the products of reaction 1, corresponding to electrontransfer, may also arise via charge-transfer at a crossing point without proceeding through a long-lived complex. Previous ion/ion reaction studies involving multiply charged ions have suggested that charge-transfer at crossing points without long-lived complex formation can contribute significantly, in at least some cases, to electron-transfer [13][14][15]. Reactions 2 and 3, on the other hand, are expected to proceed via a long-lived complex.…”

Section: Computational Chemistrymentioning

confidence: 99%

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Gas-phase ion/ion reactions of transition metal complex cations with multiply charged oligodeoxynucleotide anions

Barlow

Hodges

Xia

et al. 2008

J. Am. Soc. Mass Spectrom.

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Multiply deprotonated hexadeoxyadenylate anions, (A 6 ϪnH) nϪ , where n ϭ 3-5, have been subjected to reaction with a range of divalent transition-metal complex cations in the gas phase. The cations studied included the bis-and tris-1,10-phenanthroline complexes of Cu II , Fe II , and Co II , as well as the tris-1,10-phenanthroline complex of Ru II . In addition, the hexadeoxyadenylate anions were subjected to reaction with the singly charged Fe III and Co III N,N=-ethylenebis(salicylideneiminato) complexes. The major competing reaction channels are electron-transfer from the oligodeoxynucleotide anion to the cation, the formation of a complex between the anion and cation, and the incorporation of the transition-metal into the oligodeoxynucleotide. The latter process proceeds via the anion/cation complex and involves displacement of the ligand(s) in the transition-metal complex by the oligodeoxynucleotide. Competition between the various reaction channels is governed by the identity of the transition-metal cation, the coordination environment of the metal complex, and the oligodeoxynucleotide charge state. In the case of the divalent metal phenanthroline complexes, competition between electron-transfer and metal ion incorporation is particularly sensitive to the coordination number of the reagent metal complexes. Both electron-transfer and metal ion incorporation occur to significant extents with the bis-phenanthroline ions, whereas the trisphenanthroline ions react predominantly by metal ion incorporation. To our knowledge this work reports the first observations of the gas-phase incorporation of multivalent transition-metal cations into oligodeoxynucleotide anions and represents a means for the selective incorporation of transition-metal counter-ions into gaseous oligodeoxynucleotides. [6 -8] have allowed the formation of gas-phase ions of biopolymers, including oligodeoxynucleotides (ODNs), making these ions amenable to study by mass spectrometry. Like peptides and proteins, ODNs are amphoteric, [9] allowing formation of either positively or negatively charged ions. Formation of negatively charged oligonucleotides is quite facile using ESI and, as a result, negatively charged ODN ions have been the most widely studied [9]. Oligodeoxynucleotide ions with bound metals formed by MALDI or ESI, especially those containing transition metals, have shown fragmentation behavior, which is distinct and complementary to that of ions devoid of metals [6 -8].The study of the interaction of transition metals with DNA is of critical importance, given the variety of roles such interactions fulfill. Transition-metal complexes display nuclease activity and consequently complexes such as (methidium-propyl-EDTA)iron(II) have been utilized as footprinting agents [10]. Ruthenium(II) complexes have been extensively examined as spectroscopic probes of local DNA structure [11,12]. The mechanism of action of the chemotherapeutic agent cisplatin involves binding to DNA to prevent replication [13][14][15]. Mass spectrometry has been u...

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Section: Computational Chemistrymentioning

confidence: 99%

“…Ruthenium(II) complexes have been extensively examined as spectroscopic probes of local DNA structure [11,12]. The mechanism of action of the chemotherapeutic agent cisplatin involves binding to DNA to prevent replication [13][14][15]. Mass spectrometry has been used as a tool for the examination of ODN complexes with metal ions [16].…”

mentioning

confidence: 99%

Gas-phase ion/ion reactions of transition metal complex cations with multiply charged oligodeoxynucleotide anions

Barlow

Hodges

Xia

et al. 2008

J. Am. Soc. Mass Spectrom.

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“…These complexes selectively bind to proteins or inhibit enzymes known to be overexpressed in many types of cancer. 7,[9][10][11][12][13] To date, much work has been done to elucidate the mode of action of various ruthenium-based drug candidates, 14,15 but the way they exert their antitumoural or antimetastatic effects is not yet fully understood, even for NAMI-A and NKP-1339, which have successfully completed clinical trials. 14,[16][17][18] By analogy with platinum complexes, it was originally assumed that DNA binding was the main reason for the anticancer activity of ruthenium complexes.…”

Section: Introductionmentioning

confidence: 99%

Interactions of arene ruthenium metallaprisms with human proteins

2015

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Interactions between three hexacationic arene ruthenium metallaprisms, [( p-cymene) 6+ , and a series of human proteins including human serum albumin, transferrin, cytochrome c, myoglobin and ubiquitin have been studied using NMR spectroscopy, mass spectrometry and circular dichroism spectroscopy. All data suggest that no covalent adducts are formed between the proteins and the metallaprisms. Indeed, in most cases electrostatic interactions, leading to precipitation of protein-metallaprism aggregates, have been observed. In addition, with the smallest proteins, ubiquitin, myoglobin and cytochrome c, the presence of the hexacationic arene ruthenium metallaprisms induces structural changes of the proteins, as emphasized by circular dichroism. The results suggest that proteins are certainly a biological target for these metalla-assemblies.

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“…Ruthenium compounds are currently considered the most likely candidates for the next generation of metal-based anticancer drugs [2,3]. Two representatives of this class of compounds have entered clinical trials so far: imidazolium trans-[tetrachlorido(dimethylsulfoxide)(1H-imidazole)ruthenate(III)] (NAMI-A) [4,5] and indazolium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] (KP1019) [6][7][8] (see Chart 1 for structures).…”

Section: Introductionmentioning

confidence: 99%

Characterization of the binding sites of the anticancer ruthenium(III) complexes KP1019 and KP1339 on human serum albumin via competition studies

et al. 2012

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Indazolium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] (KP1019) and its Na + analogue (KP1339) are two of the most prominent non-platinum antitumor metal complexes currently undergoing clinical trials. After intravenous administration, they are known to bind to human serum albumin (HSA) in a non-covalent manner. In order to elucidate their HSA binding sites, displacement reactions with the established site markers warfarin and dansylglycine as well as bilirubin were monitored by spectrofluorimetry, ultrafiltration−UV-vis spectrophotometry and/or capillary zone electrophoresis. Conditional stability constants for the binding of KP1019 and KP1339 to sites I and II of HSA were determined, indicating that both Ru(III) compounds bind into both sites with moderately to strong affinity (logK 1 ' = 5.3-5.8). No preference for either binding site was found and similar results were obtained for both metal complexes, demonstrating low influence of the counter ion on the binding event.

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Metal-based antitumour drugs in the post genomic era

Cited by 737 publications

References 39 publications

Gas-phase ion/ion reactions of transition metal complex cations with multiply charged oligodeoxynucleotide anions

Gas-phase ion/ion reactions of transition metal complex cations with multiply charged oligodeoxynucleotide anions

Interactions of arene ruthenium metallaprisms with human proteins

Characterization of the binding sites of the anticancer ruthenium(III) complexes KP1019 and KP1339 on human serum albumin via competition studies

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