Anti-cancer organoruthenium(<scp>ii</scp>) complexes and their interactions with cysteine and its analogues. A mass-spectrometric study

Briš, Anamarija; Jašík, Juraj; Turel, Iztok; Roithová, Jana

doi:10.1039/c8dt04350g

Cited by 21 publications

(20 citation statements)

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“…The thiol groups of the cysteine residues are the most reactive sites for metallodrug binding . Therefore, the amount of thiol of NCp7 was measured in the reaction with Ru agents.…”

Section: Resultssupporting

confidence: 93%

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Covalent versus Noncovalent Binding of Ruthenium η⁶‐p‐Cymene Complexes to Zinc‐Finger Protein NCp7

Sheng

Hou

Cui

et al. 2019

Chemistry A European J

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Ruthenium-arene complexesa re au nique class of organometallic compounds that have been shown to have prominent therapeutic potencies.H ere, we have investigated the interactions of Ru-cymene complexes with az incfinger protein NCp7, aiming to understand the effects of various ligandso nt he reaction. Five different binding modes were observed on selected Ru-complexes. Ru-cymene complex can bind to proteins through either noncovalent binding aloneo rt hrough ac ombinationo fc ovalent and nonco-valentb inding modes. Moreover,t he noncovalent interaction can promote the coordination of Ru II to NCp7, resulting synergistic effects of the different ligands. The binding of Ru(Cym) complexes leads to dysfunction of NCp7 through zinc-ejection and structural perturbation. These results indicate that the reactivityo fR u-complexes can be modulated by ligands through differenta pproaches, which could be closely correlated to their different therapeutic effects.

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“…The thiol groups of the cysteine residues are the most reactive sites for metallodrug binding . Therefore, the amount of thiol of NCp7 was measured in the reaction with Ru agents.…”

Section: Resultssupporting

confidence: 93%

“…Only cymene ligand was observed in the product of Ru‐1 and Ru‐5 , indicating the release of the chlorido and Cl‐dkt during the protein reactions. These results are consistent with the reported data that pta and Cq ligands are more inert than chlorido and Cl‐dkt in the substitution of Ru II agents …”

Section: Resultsmentioning

confidence: 99%

Covalent versus Noncovalent Binding of Ruthenium η⁶‐p‐Cymene Complexes to Zinc‐Finger Protein NCp7

Sheng

Hou

Cui

et al. 2019

Chemistry A European J

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“…It seems like it is a general trend that chlorido ligand is easier exchanged with water than the pta ligand, i.e., chlorido ligand is more labile than pta. This also affects the kinetics of interactions with biomolecules and thus, also their biological activity [43][44][45].…”

Section: Kinetics Of the Interaction Of Ru Complex (1) And (2) With Hmentioning

confidence: 99%

Binding Kinetics of Ruthenium Pyrithione Chemotherapeutic Candidates to Human Serum Proteins Studied by HPLC-ICP-MS

et al. 2020

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The development of ruthenium-based complexes for cancer treatment requires a variety of pharmacological studies, one of them being a drug’s binding kinetics to serum proteins. In this work, speciation analysis was used to study kinetics of ruthenium-based drug candidates with human serum proteins. Two ruthenium (Ru) complexes, namely [(η6-p-cymene)Ru(1-hydroxypyridine-2(1H)-thionato)Cl] (1) and [(η6-p-cymene)Ru(1-hydroxypyridine-2(1H)-thionato)pta]PF6 (2) (where pta = 1,3,5-triaza-7-phosphaadamantane), were selected. Before a kinetics study, their stability in relevant media was confirmed by nuclear magnetic resonance (NMR). Conjoint liquid chromatography (CLC) monolithic column, assembling convective interaction media (CIM) protein G and diethylamino (DEAE) disks, was used for separation of unbound Ru species from those bound to human serum transferrin (Tf), albumin (HSA) and immunoglobulins G (IgG). Eluted proteins were monitored by UV spectrometry (278 nm), while Ru species were quantified by post-column isotope dilution inductively coupled plasma mass spectrometry (ID-ICP-MS). Binding kinetics of chlorido (1) and pta complex (2) to serum proteins was followed from 5 min up to 48 h after incubation with human serum. Both Ru complexes interacted mainly with HSA. Complex (1) exhibited faster and more extensive interaction with HSA than complex (2). The equilibrium concentration for complex (1) was obtained 6 h after incubation, when about 70% of compound was bound to HSA, 5% was associated with IgG, whereas 25% remained unbound. In contrast, the rate of interaction of complex (2) with HSA was much slower and less extensive and the equilibrium concentration was obtained 24 h after incubation, when about 50% of complex (2) was bound to HSA and 50% remained unbound.

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“…These molecules can, however, also react with metallodrugs possessing labile ligands [39]. In our previous studies, we have found that the behavior of the complexes depends on the type of the ligand and together with all above mentioned factors affect the kinetics of interactions with biomolecules, and thus, also their biological activity [40][41][42]. Previously, we have already reported stability investigations of some organoruthenium(II)-pyrithionato complexes [22,24,32] as well as of structurally related organoruthenium(II) compounds [40][41][42] by NMR, MS, and UV-Vis spectroscopies.…”

Section: Stability Of Organoruthenium(ii) Pyrithione Complexesmentioning

confidence: 99%

“…An additional evidence was provided by electrospray ionization-mass spectrometry (ESI-MS), taking advantage by sensitivity and soft ionization method of this technique, which allows to reveal non-covalent interactions with an efficient detection across a range of solvents, which we have already reported in some similar systems for organoruthenium(II) compounds [41,42]. In detail, ESI-MS analysis was carried out in positive ion mode by direct infusion from an aqueous solution of 1b prepared immediately before measurement and after three days.…”

Section: Stability Of Organoruthenium(ii) Pyrithione Complexesmentioning

confidence: 99%

Structural Isomerism and Enhanced Lipophilicity of Pyrithione Ligands of Organoruthenium(II) Complexes Increase Inhibition on AChE and BuChE

Kladnik

Ristovski

Kljun

et al. 2020

IJMS

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The increasing number of Alzheimer’s disease (AD) cases requires the development of new improved drug candidates, possessing the ability of more efficient treatment as well as less unwanted side effects. Cholinesterase enzymes are highly associated with the development of AD and thus represent important druggable targets. Therefore, we have synthesized eight organoruthenium(II) chlorido complexes 1a–h with pyrithione-type ligands (pyrithione = 1-hydroxypyridine-2(1H)-thione, a), bearing either pyrithione a, its methyl (b-e) or bicyclic aromatic analogues (f–h) and tested them for their inhibition towards electric eel acetylcholinesterase (eeAChE) and horse serum butyrylcholinesterase (hsBuChE). The experimental results have shown that the novel complex 1g with the ligand 1-hydroxyquinoline-2-(1H)-thione (g) improves the inhibition towards eeAChE (IC50 = 4.9 μM) and even more potently towards hsBuChE (IC50 = 0.2 μM) in comparison with the referenced 1a. Moreover, computational studies on Torpedo californica AChE have supported the experimental outcomes for 1g, possessing the lowest energy value among all tested complexes and have also predicted several interactions of 1g with the target protein. Consequently, we have shown that the aromatic ring extension of the ligand a, though only at the appropriate position, is a viable strategy to enhance the activity against cholinesterases.

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Anti-cancer organoruthenium(ii) complexes and their interactions with cysteine and its analogues. A mass-spectrometric study

Abstract: ESI-MS study of ruthenium complexes shows their high selectivity toward thiol containing molecules and formation of larger thiolate-bound clusters in absence of a protecting ligand such as pta.

Cited by 21 publications

References 50 publications

Covalent versus Noncovalent Binding of Ruthenium η⁶‐p‐Cymene Complexes to Zinc‐Finger Protein NCp7

Covalent versus Noncovalent Binding of Ruthenium η⁶‐p‐Cymene Complexes to Zinc‐Finger Protein NCp7

Binding Kinetics of Ruthenium Pyrithione Chemotherapeutic Candidates to Human Serum Proteins Studied by HPLC-ICP-MS

Structural Isomerism and Enhanced Lipophilicity of Pyrithione Ligands of Organoruthenium(II) Complexes Increase Inhibition on AChE and BuChE

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Anti-cancer organoruthenium(ii) complexes and their interactions with cysteine and its analogues. A mass-spectrometric study

Abstract: ESI-MS study of ruthenium complexes shows their high selectivity toward thiol containing molecules and formation of larger thiolate-bound clusters in absence of a protecting ligand such as pta.

Cited by 21 publications

References 50 publications

Covalent versus Noncovalent Binding of Ruthenium η6‐p‐Cymene Complexes to Zinc‐Finger Protein NCp7

Covalent versus Noncovalent Binding of Ruthenium η6‐p‐Cymene Complexes to Zinc‐Finger Protein NCp7

Binding Kinetics of Ruthenium Pyrithione Chemotherapeutic Candidates to Human Serum Proteins Studied by HPLC-ICP-MS

Structural Isomerism and Enhanced Lipophilicity of Pyrithione Ligands of Organoruthenium(II) Complexes Increase Inhibition on AChE and BuChE

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Covalent versus Noncovalent Binding of Ruthenium η⁶‐p‐Cymene Complexes to Zinc‐Finger Protein NCp7

Covalent versus Noncovalent Binding of Ruthenium η⁶‐p‐Cymene Complexes to Zinc‐Finger Protein NCp7