New Insights into the Redox Chemistry of Ruthenium Metallopharmaceuticals: The Electrochemical Behaviour of [LH][trans‐RuIIICl4L2] (L = imidazole or indazole) Complexes

Ravera, Mauro; Cassino, Claudio; Baracco, Sara; Osella, Domenico

doi:10.1002/ejic.200500634

Cited by 10 publications

(15 citation statements)

References 18 publications

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“…Osella and co-workers reported that ICR (as sodium salt) is reduced in vitro within min-utes by a two-fold excess of glutathione at 37.0 °C in a pH range from 4.0 to 7.4. [19] In contrast, Keppler and co-workers [20] established that ICR is reduced by an excess of gluthatione or ascorbic acid only at pH 7.4 but not, contrary to a previous report, [21] in pure water. Conversely, the redox potential of the indazole derivative KP1019 was found to be remarkably higher than that of ICR, ca.…”

Section: Chemical Behavior and Activation Of Nami-amentioning

confidence: 82%

Ruthenium Anticancer Compounds: Challenges and Expectations

Bratsos¹,

Jedner²,

Gianferrara³

et al. 2007

Chimia

214

142

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Two ruthenium compounds, namely [ImH]trans-[RuCl4(Im)(dmso-S)] (NAMI-A, Im = imidazole) and [IndH] trans-[RuCl4(Ind)2] (KP1019, Ind = indazole) have already completed phase I clinical trials as anticancer agents. They both have properties different from platinum anticancer drugs: for example, NAMI-A is selectively active against metastases of solid tumors. They show that in the field of anticancer metal drugs a new approach, based on targeted therapies, is possible. After a concise history of ruthenium anticancer compounds, this contribution will focus on ruthenium-dmso complexes and, in particular, on NAMI-A. Particular emphasis is given on the challenges that are inherent to this field: how to develop new anticancer ruthenium compounds and how to select new active compounds that manifest their anticancer activity through non-conventional mechanisms.

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Section: Chemical Behavior and Activation Of Nami-amentioning

confidence: 82%

Ruthenium Anticancer Compounds: Challenges and Expectations

Bratsos¹,

Jedner²,

Gianferrara³

et al. 2007

Chimia

214

142

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“…22,23 For the KP1019 complex, it is also observed an increase in the reduction potential after the first hydrolysis. Ravera et al 25 measured the reduction potential of [Ru III (H 2 O)Cl 3 (Ind) 2 ] at -0.072 V vs. Ag/AgCl, which corresponds to an increase of 0.088 V compared with the KP1019 reduction potential. Therefore, the trend observed in our computed values for NAMI-A and its hydrolysis products are in line with the experimental findings and shows that it is easier to reduce the hydrolyzed products than the original compound.…”

Section: Resultsmentioning

confidence: 99%

“…Electrochemical and chemical reduction studies of Ru III metallodrugs are, therefore, of great importance in order to understand their biological activities and thus have been the subject of several studies. [18][19][20][21][22][23][24][25][26][27] Ravera et al 25 investigated the redox chemistry of [LH][trans-Ru III Cl 4 L 2 ] (L = imidazole or indazole) complexes in water at different pH values. For the indazole and imidazole complexes the E 0 ' (Ru III /Ru II ) reduction potential of -0.160 and -0.460 V vs. Ag/AgCl was obtained at pH 4.0.…”

Section: Introductionmentioning

confidence: 99%

Reduction Potential of RuIII-Based Complexes with Potential Antitumor Activity and Thermodynamics of their Hydrolysis Reactions and Interactions with Possible Biological Targets: a Theoretical Investigation

Pereira

Chagas

Rocha

2018

J. Braz. Chem. Soc.

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In this article density functional theory (DFT)-based calculations were employed to investigate the electrochemistry of the antitumor ruthenium complexes trans-tetrachloro(dimethylsulfoxide) imidazole ruthenate(III) (NAMI-A) and trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019), their hydrolysis products as well as their interactions with biological S-donors and N-donors targets as cysteine, glutathione and guanine nucleobase. The compounds exhibit different electrochemical behavior upon hydrolysis. While the reduction potential of NAMI-A increases up to 0.8 V upon hydrolysis, the reduction potential of KP1019 remains almost constant after the first hydrolysis. NAMI-A and KP1019 complexes have thermodynamic preference to be reduced prior to undergoing hydrolysis and, strong preference to undergo successive hydrolysis instead of interacting with the S-donor and N-donor ligands. Interaction with S-donor ligands in the unprotonated form is highly unfavorable, with the free energy in solution (ΔG sol) ≥ 18 kcal mol-1. For both complexes, the interaction with the guanine and glutathione are of the same magnitude (ΔG sol ca.-0.6 kcal mol-1) meaning that these ligands can compete for binding to the metallodrug.

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“…7 In contrast, ICR would need stronger reductants, which may be more rare in a biological environment. 3,21,25 Consistently, ICR has proved to be more inert than NAMI-A, and its hydrolysis path is less affected by reductants. 26 Recently, Chen et al have reported a theoretical investigation on NAMI-A and ICR hydrolyses, 27,28 focusing on Cldissociation.…”

Section: Introductionmentioning

confidence: 88%

“…6,7 Furthermore, the hydrolysis of the reduced compounds has not been considered, even though it may be important for both drugs because of the high reducing power of solid tumor tissues. 21,29 In order to understand the mechanism of action of NAMI-A and ICR at the molecular level, an extensive investigation of the hydrolysis paths in both Ru oxidation states, along with an evaluation of the reduction potentials of the two drugs and their metabolites, is needed. In this work we tackle this issue and report a systematic study of the hydrolyses of the two drugs up to the third aquation, combining density functional theory (DFT) calculations and an implicit description of the solvent through the conductor-like polarizable continuum model (CPCM).…”

Section: Introductionmentioning

confidence: 99%

The Hydrolysis Mechanism of the Anticancer Ruthenium Drugs NAMI-A and ICR Investigated by DFT−PCM Calculations

et al. 2008

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(ImH)[trans-RuCl(4)(DMSO-S)(Im)], (Im = imidazole, DMSO-S = S-bonded dimethylsulfoxide), NAMI-A, is the first anticancer ruthenium compound that successfully completed Phase I clinical trials. NAMI-A shows a remarkable activity against lung metastases of solid tumors, but is not effective in the reduction of primary cancer. The structurally similar (ImH)[trans-RuCl(4)(Im)(2)], ICR (or KP418), and its indazole analog (KP1019) are promising candidate drugs in the treatment of colorectal cancers, but have no antimetastatic activity. Despite the pharmacological relevance of these compounds, no rationale has been furnished to explain their markedly different activity. While the nature of the chemical species responsible for their antimetastatic/anticancer activity has not been determined, it has been suggested that the difference between reduction potentials of NAMI-A and ICR may be the key to the different biological responses they induce. In this work, Density Functional Theory calculations were performed to investigate the hydrolysis of NAMI-A and ICR in both Ru(III) and Ru(II) oxidation states, up to the third aquation. In line with experimental findings, our calculations provide a picture of the hydrolysis of NAMI-A and ICR mainly as a stepwise loss of chloride ligands. While dissociation of Im is unlikely under neutral conditions, that of DMSO becomes competitive with the loss of chloride ions as the hydrolysis proceeds. Redox properties of NAMI-A and ICR and of their most relevant hydrolytic intermediates were also studied in order to monitor the effects of biological reductants on the mechanism of action. Our findings may contribute to the identification of the active compounds that interact with biological targets, and to explain the different biological activity of NAMI-A and ICR.

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New Insights into the Redox Chemistry of Ruthenium Metallopharmaceuticals: The Electrochemical Behaviour of [LH][trans‐Ru^IIICl₄L₂] (L = imidazole or indazole) Complexes

Cited by 10 publications

References 18 publications

Ruthenium Anticancer Compounds: Challenges and Expectations

Ruthenium Anticancer Compounds: Challenges and Expectations

Reduction Potential of RuIII-Based Complexes with Potential Antitumor Activity and Thermodynamics of their Hydrolysis Reactions and Interactions with Possible Biological Targets: a Theoretical Investigation

The Hydrolysis Mechanism of the Anticancer Ruthenium Drugs NAMI-A and ICR Investigated by DFT−PCM Calculations

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