Structural isomerism of Ru(<scp>ii</scp>)-carbonyl complexes: synthesis, characterization and their antitrypanosomal activities

Barbosa, Marília Imaculada Frazão; Corrêa, Rodrigo S.; Bastos, Tanira Matutino; Pozzi, Lucas V.; Moreira, Diogo Rodrigo de Magalhães; Ellena, Javier; Silveira, Rafael G.; Oliveira, César R. de; Kuznetsov, Aleksey E.; Malta, V. R. S.; Soares, Milena Botelho Pereira; Batista, Alzir A.

doi:10.1039/c7nj00125h

Cited by 14 publications

(7 citation statements)

References 35 publications

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“…Our research group evaluated the release of the CO molecule from ct‐ [RuCl(CO)(dppb)(bipy)]PF 6 by 13 C{ 1 H} NMR (DMSO‐d 6 ) and cyclic voltammetry. In that study, the compound exhibited a d 5 configuration after its oxidation from ruthenium(II) to (III) (after 48 hours), destabilizing the Ru‐CO bond and allowing dissociation of the CO molecule from the compound in the biological medium (Barbosa et al, ).…”

Section: Discussionmentioning

confidence: 97%

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Study of the cytotoxic and genotoxic potential of the carbonyl ruthenium(II) compound, ct‐[RuCl(CO)(dppb)(bipy)]PF₆ [dppb = 1,4‐bis(diphenylphosphino)butane and bipy = 2,2′‐bipyridine], by in vitro and in vivo assays

Carnizello

Alves

Pereira

et al. 2018

J of Applied Toxicology

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Considering the promising previous results of ct‐[RuCl(CO)(dppb)(bipy)]PF6 (where dppb = 1,4‐bis(diphenylphosphino)butane and bipy = 2,2′‐bipyridine) as an antitumor agent, novel biological assays evaluating its toxicogenic potential were performed. The genotoxicity of the compound was evaluated by the in vitro micronucleus test (V79, Chinese hamster lung fibroblasts; HepG2, hepatocellular carcinoma cells), in vivo bone marrow micronucleus test and comet assay in hepatocytes (Swiss mice). The animals were treated with 0.63, 1.25, 2.5 and 5.0 mg/kg body weight (bw) of the compound. Negative (water) and positive (cisplatin, 1.5 mg/kg bw; methyl methanesulfonate, 40 mg/kg bw) controls were included. The parameters considered in the comet assay were the percentage of tail DNA, tail moment and tail length. The results of the in vitro micronucleus tests showed the absence of genotoxicity in V79 cells, while the compound was genotoxic in HepG2 cells at a concentration of 1.25 μm. In the in vivo micronucleus test, the compound was not genotoxic at the different doses evaluated. In the comet assay, only the dose of 5.0 mg/kg bw resulted in a significant increase in the frequency of DNA damage in hepatocytes when compared to the negative control. The genotoxic effect observed in HepG2 cells and in the liver comet assay indicates that the compound was metabolized by hepatic cells.

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Section: Discussionmentioning

confidence: 97%

“…cyclic voltammetry. In that study, the compound exhibited a d 5 configuration after its oxidation from ruthenium(II) to (III) (after 48 hours), destabilizing the Ru-CO bond and allowing dissociation of the CO molecule from the compound in the biological medium (Barbosa et al, 2017).…”

Section: Comet Assaymentioning

confidence: 94%

Study of the cytotoxic and genotoxic potential of the carbonyl ruthenium(II) compound, ct‐[RuCl(CO)(dppb)(bipy)]PF₆ [dppb = 1,4‐bis(diphenylphosphino)butane and bipy = 2,2′‐bipyridine], by in vitro and in vivo assays

Carnizello

Alves

Pereira

et al. 2018

J of Applied Toxicology

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“…It is worth pointing out that the arene ruthenium complexes which have been investigated as promising anticancer drugs [33–35] can be involved in the disruption of the cellular redox homeostasis via NADH transfer hydrogenation, as well as GSH metal thiol binding and oxidation [36] . Conversely, only few studies have been reported on the use of diphosphine ruthenium hydrogenation catalysts as efficient anticancer systems [37–40] …”

Section: Introductionmentioning

confidence: 99%

“…[36] Conversely, only few studies have been reported on the use of diphosphine ruthenium hydrogenation catalysts as efficient anticancer systems. [37][38][39][40] Herein we report the isolation of the cationic enantiomer complexes [RuX(CO)(PP)(phen)]Y (X, Y = carboxylates, thioacetate, PP = (R,R)-or (S,S)-Skewphos) [21] and their behaviour with (S)-cysteine and GSH via formation of aquo complexes. Remarkably different and very promising cytotoxic activity toward several cell lines has been observed for the couples of enantiomers.…”

Section: Introductionmentioning

confidence: 99%

Enantioselective Cytotoxicity of Chiral Diphosphine Ruthenium(II) Complexes Against Cancer Cells

Lovison

Alessi

Allegri

et al. 2022

Chemistry A European J

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The chiral cationic complex [Ru(η1‐OAc)(CO)((R,R)‐Skewphos)(phen)]OAc (2R), isolated from reaction of [Ru(η1‐OAc)(η2‐OAc)(R,R)‐Skewphos)(CO)] (1R) with phen, reacts with NaOPiv and KSAc affording [RuX(CO)((R,R)‐Skewphos)(phen)]Y (X=Y=OPiv 3R; X=SAc, Y=OAc 4R). The corresponding enantiomers 2S‐4S have been obtained from 1S containing (S,S)‐Skewphos. Reaction of 2R and 2S with (S)‐cysteine and NaPF6 at pH=9 gives the diastereoisomers [Ru((S)‐Cys)(CO)(PP)(phen)]PF6 (PP=(R,R)‐Skewphos 2R‐Cys; (S,S)‐Skewphos 2S‐Cys). The DFT energetic profile for 2R with (S)‐cysteine in H2O indicates that aquo and hydroxo species are involved in formation of 2R‐Cys. The stability of the ruthenium complexes in 0.9 % w/v NaCl solution, PBS and complete DMEM medium, as well as their n‐octanol/water partition coefficient (logP), have been evaluated. The chiral complexes show high cytotoxic activity against SW1736, 8505 C, HCT‐116 and A549 cell lines with EC50 values of 2.8–0.04 μM. The (R,R)‐Skewphos derivatives show higher cytotoxicity compared to their enantiomers, 4R (EC50=0.04 μM) being 14 times more cytotoxic than 4S against the anaplastic thyroid cancer 8505 C cell line.

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“…However, to the best of our knowledge, they have never been tested in TH reactions with the NAD + /NADH couple. Recent studies also showed that this family of compounds are endowed with antiproliferative activity in cancer cells [33][34][35][36][37] . Therefore, we synthesized three Ru(II) monocarbonyl compounds (Scheme 1, complexes 1-3) featuring the same bidentate phosphine 1,4-bis(diphenylphosphino)butane (dppb) but different N^N ligands -namely ,2'-bipyridine (bipy), 1,10-phenanthroline (phen) and pyrazino [2,3-f] [1,10]phenanthroline (pzphen) -to explore the effects of the different aromatic scaffolds on the catalytic activity of the compounds.…”

Section: Introductionmentioning

confidence: 95%

Beyond Metal-Arenes: Monocarbonyl Ruthenium(II) Catalysts for Transfer Hydrogenation Reactions in Cancer Cells

Lovison

Berghausen

Thomas

et al. 2023

Preprint

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With the aim to design new water-soluble organometallic Ru(II) complexes acting as anticancer agents catalysing transfer hydrogenation (TH) reactions with biomolecules, we have synthesized four Ru(II) monocarbonyl complexes (1-4) featuring the 1,4-bis(diphenylphosphino)butane (dppb) ligand and different bidentate nitrogen (N^N) ligands, of general formula [Ru(OAc)CO(dppb)(N^N)]n (n = +1, 0; OAc = acetate). The compounds have been characterised by different methods, including 1H and 31P NMR spectroscopy, electrochemistry as well as single crystals X-ray diffraction in the case of 1 and 4. The compounds have also been studied for their hydrolysis in aqueous environment, and for the catalytic regioselective reduction of NAD+ to 1,4-NADH in aqueous solution with sodium formate as hydride source. Moreover, the stoichiometric and catalytic oxidation of 1,4-NADH have also been investigated by UV-Visible spectrophotometry and NMR spectroscopy. Overall, initial structure-activity relationships could be inferred which point towards the influence of the extension of the aromatic N^N ligand in the cationic complexes 1-3 on the TH in both reduction/oxidation processes. The neutral complex 4, featuring a picolinamidate N^N ligand, stands out as the most active catalyst for the reduction of NAD+, while being completely inactive towards NADH oxidation. The compound can also convert pyruvate into lactate in the presence of formate, albeit with scarce efficiency. In any case, for all compounds, Ru(II) hydride intermediates could be observed and even isolated in the case of complexes 1-3. Together, insight from the kinetic and electrochemical characterization suggests that, in the case of Ru(II) complexes 1-3, catalytic NADH oxidation sees the H-transfer from 1,4-NADH as the rate limiting step, whereas for NAD+ hydrogenation with formate as the H-donor, the rate limiting step is the transfer of the ruthenium hydride to the NAD+ substrate. The latter is further modulated by the presence of di-cationic aquo- or mono-cationic hydroxo-species of complexes 1-3. Instead, compound 4, stable with respect to hydrolysis in aqueous solution, appears to operate via a different mechanism. Finally, the anticancer activity and ability to form reactive oxygen species (ROS) of complexes 1-3 have been studied in cancerous and non-tumorigenic cells in vitro. Noteworthy, the conversion of aldehydes to alcohols could be achieved by the three Ru(II) catalysts in living cells, as assessed by fluorescence microscopy. Furthermore, the formation of Ru(II) hydride intermediate upon treatment of cancer cell extracts with complex 3 has been detected by 1H NMR spectroscopy. Overall, this study paves the way to the application of non-arene based organometallic complexes as TH catalysts in biological environment.

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Structural isomerism of Ru(ii)-carbonyl complexes: synthesis, characterization and their antitrypanosomal activities

Abstract: New complexes with the formula [RuCl(CO)(dppb)(N–N)]PF6 were prepared by varying the CO position as well as the diimine ligand.

Cited by 14 publications

References 35 publications

Study of the cytotoxic and genotoxic potential of the carbonyl ruthenium(II) compound, ct‐[RuCl(CO)(dppb)(bipy)]PF₆ [dppb = 1,4‐bis(diphenylphosphino)butane and bipy = 2,2′‐bipyridine], by in vitro and in vivo assays

Study of the cytotoxic and genotoxic potential of the carbonyl ruthenium(II) compound, ct‐[RuCl(CO)(dppb)(bipy)]PF₆ [dppb = 1,4‐bis(diphenylphosphino)butane and bipy = 2,2′‐bipyridine], by in vitro and in vivo assays

Enantioselective Cytotoxicity of Chiral Diphosphine Ruthenium(II) Complexes Against Cancer Cells

Beyond Metal-Arenes: Monocarbonyl Ruthenium(II) Catalysts for Transfer Hydrogenation Reactions in Cancer Cells

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Structural isomerism of Ru(ii)-carbonyl complexes: synthesis, characterization and their antitrypanosomal activities

Abstract: New complexes with the formula [RuCl(CO)(dppb)(N–N)]PF6 were prepared by varying the CO position as well as the diimine ligand.

Cited by 14 publications

References 35 publications

Study of the cytotoxic and genotoxic potential of the carbonyl ruthenium(II) compound, ct‐[RuCl(CO)(dppb)(bipy)]PF6 [dppb = 1,4‐bis(diphenylphosphino)butane and bipy = 2,2′‐bipyridine], by in vitro and in vivo assays

Study of the cytotoxic and genotoxic potential of the carbonyl ruthenium(II) compound, ct‐[RuCl(CO)(dppb)(bipy)]PF6 [dppb = 1,4‐bis(diphenylphosphino)butane and bipy = 2,2′‐bipyridine], by in vitro and in vivo assays

Enantioselective Cytotoxicity of Chiral Diphosphine Ruthenium(II) Complexes Against Cancer Cells

Beyond Metal-Arenes: Monocarbonyl Ruthenium(II) Catalysts for Transfer Hydrogenation Reactions in Cancer Cells

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Study of the cytotoxic and genotoxic potential of the carbonyl ruthenium(II) compound, ct‐[RuCl(CO)(dppb)(bipy)]PF₆ [dppb = 1,4‐bis(diphenylphosphino)butane and bipy = 2,2′‐bipyridine], by in vitro and in vivo assays

Study of the cytotoxic and genotoxic potential of the carbonyl ruthenium(II) compound, ct‐[RuCl(CO)(dppb)(bipy)]PF₆ [dppb = 1,4‐bis(diphenylphosphino)butane and bipy = 2,2′‐bipyridine], by in vitro and in vivo assays