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1.
J Inorg Biochem ; 238: 112052, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36334365

RESUMO

The role of metal complexes on facing DNA has been a topic of major interest. However, metallonitrosyl compounds have been poorly investigated regarding their reactivities and interaction with DNA. A nitrosyl compound, cis-[Ru(bpy)2(SO3)(NO)](PF6)(A), showed a variety of promising biological activities catching our attention. Here, we carried out a series of studies involving the interaction and damage of DNA mediated by the metal complex A and its final product after NO release, cis-[Ru(bpy)2(SO3)(H2O](B). The fate of DNA with these metal complexes was investigated upon light or chemical stimuli using electrophoresis, electronic absorption spectroscopy, circular dichroism, size-exclusion resin, mass spectrometry, electron spin resonance (ESR) and viscometry. Since many biological disorders involve the production of oxidizing species, it is important to evaluate the reactivity of these compounds under such conditions as well. Indeed, the metal complex B exhibited important reactivity with H2O2 enabling DNA degradation, with detection of an unusual oxygenated intermediate. ESR spectroscopy detected mainly the DMPO-OOH adduct, which only emerges if H2O2 and O2 are present together. This result indicated HOO• as a key radical likely involved in DNA damage as supported by agarose gel electrophoresis. Notably, the nitrosyl ruthenium complex did not show evidence of direct DNA damage. However, its aqua product should be carefully considered as potentially harmful to DNA deserving further in vivo studies to better address any genotoxicity.


Assuntos
Complexos de Coordenação , Rutênio , Rutênio/química , Complexos de Coordenação/química , Peróxido de Hidrogênio , Compostos de Rutênio/química , Óxido Nítrico/química , DNA
2.
Nanoscale ; 14(44): 16339-16375, 2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36341705

RESUMO

Ruthenium complex is an important compound group for antitumor drug research and development. NAMI-A, KP1019, TLD1433 and other ruthenium complexes have entered clinical research. In recent years, the research on ruthenium antitumor drugs has not been limited to single chemotherapy drugs; other applications of ruthenium complexes have emerged such as in combination therapy. During the development of ruthenium complexes, drug delivery forms of ruthenium antitumor drugs have also evolved from single-molecule drugs to nanodrug delivery systems. The review summarizes the following aspects: (1) ruthenium complexes from monotherapy to combination therapy, including the development of single-molecule compounds, carrier nanomedicine, and self-assembly of carrier-free nanomedicine; (2) ruthenium complexes in the process of ADME in terms of absorption, distribution, metabolism and excretion; (3) the applications of ruthenium complexes in combination therapy, including photodynamic therapy (PDT), photothermal therapy (PTT), photoactivated chemotherapy (PACT), immunotherapy, and their combined application; (4) the future prospects of ruthenium-based antitumor drugs.


Assuntos
Antineoplásicos , Fotoquimioterapia , Rutênio , Rutênio/farmacologia , Compostos de Rutênio , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/metabolismo
3.
Anal Chim Acta ; 1227: 340310, 2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-36089320

RESUMO

In this article we describe construction of a bioreceptive interface for detection of a breast cancer biomarker carbohydrate antigen CA15-3. The conductive interface was patterned by a 2D nanomaterial MXene, to which a mixed layer containing sulfobetaine and carboxybetaine was electrochemically grafted through a diazonium moiety. Such a modified interface was then applied for covalent immobilisation of anti-CA15-3 antibody as a bioreceptive probe for detection of a breast cancer biomarker. Two different strategies were applied for final construction of an immunosensor i.e. an interface finally blocked by bovine serum albumin or an immunosensor without such modification. Finally, electrochemical reading was accomplished using a soluble redox probe Ru(NH3)63+ ion for detection of CA15-3 in a clinically relevant range up to 50 U mL-1. The results indicate that immunosensor based on non-blocked interface can be applied for biosensing using two modes of action: 1. differential pulse voltammetry (a plot of a peak current vs. analyte concentration) and 2. an electrochemical impedance spectroscopy (a plot of a charge transfer resistance vs. analyte concentration). The electrode blocked by bovine serum albumin (BSA) can be used by additional 3. mode of action: through detection of changes in the potential (a plot Epvs. c). Additionally, we reveal and explain that Ru(NH3)63+ is redox probe, which can be applied as interfacial molecular nanoscale ruler to distinguish negatively charged protein molecules present in the close proximity (≤ 6 nm) of the electrode (in our case adsorbed BSA molecules) from the negatively charged protein molecules at a larger distance (>12 nm) from the electrode (i.e. CA15-3 analyte).


Assuntos
Técnicas Biossensoriais , Neoplasias da Mama , Biomarcadores Tumorais , Técnicas Biossensoriais/métodos , Neoplasias da Mama/diagnóstico , Feminino , Humanos , Imunoensaio/métodos , Mucina-1 , Oxirredução , Compostos de Rutênio , Soroalbumina Bovina
4.
J Mol Model ; 28(10): 291, 2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36063245

RESUMO

Ruthenium (Ru)-based anticancer drugs are considered to be novel alternatives of platinum-based drugs. They exhibit potent cytotoxicity against the cancer cells and hence are useful for the treatment of cancer. Herein, the density functional theory calculations in the gas phase and aqueous media are carried out to study the reactions of two Ru(III)-based drugs such as KP1019 and KP418 with the N7 site of guanine (G), 2'-deoxyguanosine (dGua), and guanosine (Gua) to understand their reactivity against the DNA and RNA. All the reactions are found to be exothermic. The activation free energies and rate constants of these reactions indicate that KP1019 and KP418 would react with the dGua more readily than Gua. Hence, the binding of these drugs with the DNA would be more preferred as compared to RNA. It is further found that among these drugs, KP1019 would be more reactive than KP418 in agreement with the experimental observation. Thus, this study is expected to aid in the future development of potent anticancer drugs.


Assuntos
Antineoplásicos , Rutênio , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , DNA , Desoxiguanosina , Guanina/farmacologia , Guanosina/farmacologia , Indazóis , Compostos Organometálicos , RNA , Rutênio/farmacologia , Compostos de Rutênio
5.
Biomolecules ; 12(9)2022 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-36139158

RESUMO

Ruthenium complexes are at the forefront of developments in metal-based anticancer drugs, but many questions remain open regarding their reactivity in biological media, including the role of transferrin (Tf) in their transport and cellular uptake. A well-known anticancer drug, KP1019 ((IndH)[RuIIICl4(Ind)2], where Ind = indazole) and a reference complex, [RuIII(nta)2]3- (nta = nitrilotriacetato(3-)) interacted differently with human apoTf, monoFeTf, or Fe2Tf. These reactions were studied by biolayer interferometry (BLI) measurements of Ru-Fe-Tf binding to recombinant human transferrin receptor 1 (TfR1) in conjunction with UV-vis spectroscopy and particle size analysis. Cellular Ru uptake in human hepatoma (HepG2) cells was measured under the conditions of the BLI assays. The mode of Tf binding and cellular Ru uptake were critically dependent on the nature of Ru complex, availability of Fe(III) binding sites of Tf, and the presence of proteins that competed for metal binding, particularly serum albumin. Cellular uptake of KP1019 was not Tf-mediated and occurred mostly by passive diffusion, which may also be suitable for treatments of inoperable cancers by intratumoral injections. High cellular Ru uptake from a combination of [RuIII(nta)2]3- and Fe2Tf in the absence of significant Ru-Tf binding was likely to be due to trapping of Ru(III) species into the endosome during TfR1-mediated endocytosis of Fe2Tf.


Assuntos
Antineoplásicos , Compostos Organometálicos , Rutênio , Antineoplásicos/química , Compostos Férricos/metabolismo , Humanos , Indazóis/química , Compostos Organometálicos/química , Receptores da Transferrina/metabolismo , Rutênio/química , Rutênio/farmacologia , Compostos de Rutênio , Albumina Sérica , Transferrina/metabolismo
6.
Molecules ; 27(17)2022 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-36080160

RESUMO

The direct oxidation reaction of isoxazolidines plays an important role in organic chemistry, leading to the synthesis of biologically active compounds. In this paper, we report a computational mechanistic study of RuO4-catalyzed oxidation of differently N-substituted isoxazolidines 1a-c. Attention was focused on the endo/exo oxidation selectivity. For all the investigated compounds, the exo attack is preferred to the endo one, showing exo percentages growing in parallel with the stability order of transient carbocations found along the reaction pathway. The study has been supported by experimental data that nicely confirm the modeling results.


Assuntos
Compostos de Rutênio , Rutênio , Catálise , Oxirredução , Rutênio/química , Compostos de Rutênio/química
7.
J Inorg Biochem ; 236: 111986, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36084568

RESUMO

Here we present a split-enzyme sensor approach for the sequence-specific detection of metal-based drug adducts of DNA. Split ß-lactamase reporters were constructed using domain A of the High Mobility Group Box 1 protein (HMGB1a) in conjunction with zinc finger DNA-binding domains. As a proof of concept, the sensors were characterized with the well-known drug cisplatin, which forms 1,2-intrastrand crosslinks with DNA that are recognized by HMGB1a. After promising results with cisplatin, five ruthenium-based drugs were studied, four of which produced significant signal over background. These results highlight the utility of our approach for rapid screening of novel metal-based chemotherapeutic drug candidates and provide evidence that HMGB1a likely binds to DNA adducts formed by NAMI-A (imidazolium trans-tetrachlorodimethylsulfoxideimidazoleruthenate(III)), KP1019 (indazolium trans-tetrachlorodiindazoleruthenate(III)), KP418 (imidazolium trans-tetrachlorodiimidazoleruthenate(III)), and RAPTA-C (dichloro(η6-p-cymene)(1,3,5-triaza-7-phosphaadamantane)ruthenium(II)). These results thus imply a potential biologically relevant mode of action for the ruthenium-based drugs investigated herein.


Assuntos
Antineoplásicos , Compostos Organometálicos , Rutênio , Antineoplásicos/farmacologia , Cisplatino/farmacologia , DNA/química , Adutos de DNA , Compostos Organometálicos/química , Rutênio/química , Compostos de Rutênio , beta-Lactamases
8.
ChemMedChem ; 17(20): e202200444, 2022 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-36041073

RESUMO

Herein we illustrate the formation and characterization of new paramagnetic ruthenium compounds, trans-P-[RuCl(PPh3 )2 (pmt)]Cl (1) (Hpmt=1-((pyridin-2-yl)methylene)thiosemicarbazide), trans-P-[RuCl(PPh3 )2 (tmc)]Cl (2) (Htmc=1-((thiophen-2-yl)methylene)thiosemicarbazide) and a diamagnetic ruthenium complex, cis-Cl, trans-P-[RuCl2 (PPh3 )2 (btm)] (3) (btm=2-((5-hydroxypentylimino)methyl)benzothiazole). Agarose gel electrophoresis experiments of the metal compounds illustrated dose-dependent binding to gDNA by 1-3, while methylene blue competition assays suggested that 1 and 2 are also DNA intercalators. Assessment of the effects of the compounds on topoisomerase function indicated that 1-3 are capable of inhibiting topoisomerase I activity in terms of the ability to nick supercoiled plasmid DNA. The cytotoxic activities of the metal complexes were determined against a range of cancer cell lines versus a non-tumorigenic control cell line, and the complexes were, in general, more cytotoxic towards the cancer cells, displaying IC50 values in the low micromolar range. Time-dependent stability studies showed that in the presence of strong nucleophilic species (such as DMSO), the chloride co-ligands of 1-3 are rapidly substituted by the former as proven by the suppression of the substitution reactions in the presence of an excess amount of chloride ions. The metal complexes are significantly stable in both DCM and an aqueous phosphate buffer containing 2 % DMSO.


Assuntos
Antineoplásicos , Complexos de Coordenação , Compostos Organometálicos , Rutênio , Tiossemicarbazonas , Compostos de Rutênio/química , Compostos de Rutênio/metabolismo , Rutênio/farmacologia , Rutênio/química , Tiossemicarbazonas/farmacologia , Complexos de Coordenação/toxicidade , Complexos de Coordenação/química , Bases de Schiff/farmacologia , Dimetil Sulfóxido , Azul de Metileno , Substâncias Intercalantes , Cloretos , DNA Topoisomerases Tipo I/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , DNA/química , Benzotiazóis/farmacologia , Fosfatos , Compostos Organometálicos/química
9.
Int J Biol Macromol ; 209(Pt B): 2097-2108, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35504415

RESUMO

Fabrication of scaffolds for nerve regeneration is one of the most challenging topics in regenerative medicine at the moment, which is also interlinked with the development of biocompatible substrates for cells growth. This work is targeted towards the development of green biomaterial composite scaffolds for nerve cell culture applications. Hybrid scaffolds of hydroxyethyl cellulose/glycine (HEC/Gly) composite doped with different concentrations of green ruthenium oxide (RuO2) were synthesized and characterized via a combination of different techniques. X-rays diffraction (XRD) and differential scanning calorimetry (DSC) analyses showed a crystalline nature for all the samples with noticeable decrease in the peak intensity of the fabricated scaffolds as compared to that for pure glycine. Fourier transform infrared spectroscopy (FTIR) tests revealed an increase in the vibrational bands of the synthesized RuO2 containing scaffolds which are related to the functional groups of the natural plant extract (Aspalathuslinearis) used for RuO2 nanoparticles (NPs) synthesis. Scanning electron microscopy (SEM) results revealed a 3D porous structure of the scaffolds with variant features attributed to the concentration of RuO2 NPs in the scaffold. The compressive test results recorded an enhancement in mechanical properties of the fabricated scaffolds (up to 8.55 MPa), proportionally correlated to increasing the RuO2 NPs concentration in HEC/Gly composite scaffold. Our biocompatibility tests revealed that the composite scaffolds doped with 1 and 2 ml of RuO2 demonstrated the highest proliferation percentages (152.2 and 135.6%) compared to control. Finally, the SEM analyses confirmed the impressive cells attachments and differentiation onto the scaffold surfaces as evidenced by the presence of many neuron-like cells with apparent cell bodies and possessing few short neurite-like processes. The presence of RuO2 and glycine was due to their extraordinary biocompatibility due to their cytoprotective and regenerative effects. Therefore, we conclude that these scaffolds are promising for accommodation and growth of neural-like cells.


Assuntos
Glicina , Compostos de Rutênio/química , Tecidos Suporte , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Celulose/química , Celulose/farmacologia , Glicina/farmacologia , Neurônios , Porosidade , Espectroscopia de Infravermelho com Transformada de Fourier , Engenharia Tecidual , Tecidos Suporte/química
10.
Dalton Trans ; 51(19): 7658-7672, 2022 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-35510940

RESUMO

Ru(II) polypyridyl complexes are widely used in biological fields, due to their physico-chemical and photophysical properties. In this paper, a series of new chiral Ru(II) polypyridyl complexes (1-5) with the general formula {Δ/Λ-[Ru(bpy)2(X,Y-sal)]BF4} (bpy = 2,2'-bipyridyl; X,Y-sal = 5-bromosalicylaldehyde (1), 3,5-dibromosalicylaldehyde (2), 5-chlorosalicylaldehyde (3), 3,5-dichlorosalicylaldehyde (4) and 3-bromo-5-chlorosalicylaldehy (5)) were synthesized and characterized by elemental analysis, FT-IR, and 1H/13C NMR spectroscopy. Also, the structures of complexes 1 and 5 were determined by X-ray crystallography; these results showed that the central Ru atom adopts a distorted octahedral coordination sphere with two bpy and one halogen-substituted salicylaldehyde. DFT and TD-DFT calculations have been performed to explain the excited states of these complexes. The singlet states with higher oscillator strength are correlated with the absorption signals and are mainly described as 1MLCT from the ruthenium centre to the bpy ligands. The lowest triplet states (T1) are described as 3MLCT from the ruthenium center to the salicylaldehyde ligand. The theoretical results are in good agreement with the observed unstructured band at around 520 nm for complexes 2, 4 and 5. Biological studies on human cancer cells revealed that dihalogenated ligands endow the Ru(II) complexes with enhanced cytotoxicity compared to monohalogenated ligands. In addition, as far as the type of halogen is concerned, bromine is the halogen that provides the highest cytotoxicity to the synthesized complexes. All complexes induce cell cycle arrest in G0/G1 and apoptosis, but only complexes bearing Br are able to provoke an increase in intracellular ROS levels and mitochondrial dysfunction.


Assuntos
Compostos de Rutênio/química , Rutênio , Aldeídos , Halogenação , Halogênios , Humanos , Ligantes , Rutênio/química , Rutênio/farmacologia , Espectroscopia de Infravermelho com Transformada de Fourier
11.
Bioelectrochemistry ; 146: 108151, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35605452

RESUMO

Vascular endothelial growth factor (VEGF165) is a signal protein that plays a central role in the regulation of angiogenesis and can stimulate angiogenesis. The development of highly sensitive and selective detection method for VEGF165 is very important for disease diagnosis and follow-up treatment monitoring. In this study, an electrochemiluminescence (ECL) aptasensor for VEGF165 has been developed based on quench of H2O2 toward Ru(bpy)32+/TPrA ECL system and RecJf exonuclease induced target recovery and hybridization chain reaction (HCR) as amplification strategy. The presence of VEGF165 makes a large number of glucose oxidase (GOD) fixed on the electrode surface through the double signal amplification strategies. The present of GOD cause the production of a large amount of H2O2 near the electrode surface under excess amount of glucose, resulting in the inhibition of the ECL signal of Ru(bpy)32+/Au nanoparticles (Ru(bpy)32+/AuNPs) film fixed on the electrode surface. The ECL response of the designed biosensor has a good linear relationship with the logarithm of the concentration of VEGF165 in the range of 0.5 pg/mL to 500 ng/mL with a detection limit of 0.2 fg/mL. The VEGF165 in serum samples has been detected by the proposed aptasensor with satisfactory results.


Assuntos
Técnicas Biossensoriais , Nanopartículas Metálicas , 2,2'-Dipiridil , Técnicas Biossensoriais/métodos , Técnicas Eletroquímicas/métodos , Eletrodos , Glucose Oxidase , Ouro , Peróxido de Hidrogênio , Medições Luminescentes/métodos , Compostos de Rutênio , Fator A de Crescimento do Endotélio Vascular
12.
Curr Opin Chem Biol ; 68: 102143, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35483128

RESUMO

This review focuses on light-activated ruthenium anticancer compounds and the factors that influence which pathway is favored. Photodynamic therapy (PDT) is favored by π expansion and the presence of low-lying triplet excited states (e.g. 3MLCT, 3IL). Photoactivated chemotherapy (PACT) refers to light-driven ligand dissociation to give a toxic metal complex or a toxic ligand upon photo substitution. This process is driven by steric bulk near the metal center and weak metal-ligand bonds to create a low-energy 3MC state with antibonding character. With protic dihydroxybipyridine ligands, ligand charge can play a key role in these processes, with a more electron-rich deprotonated ligand favoring PDT and an electron-poor protonated ligand favoring PACT in several cases.


Assuntos
Complexos de Coordenação , Rutênio , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Ligantes , Rutênio/química , Rutênio/farmacologia , Compostos de Rutênio , Oxigênio Singlete/química
13.
J Inorg Biochem ; 229: 111731, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35131616

RESUMO

Metal complexes studied to date under the framework of metalloglycomics belong to the M-NH3 general motif (polynuclear platinum compounds; Werner's complex), acting mainly as cationic hydrogen bonding species toward glycosaminoglycans (GAGs), an interaction termed metalloshielding. In this paper, we expand our studies to substitution-inert octahedral cobalt(III) and ruthenium(II) complexes bearing the non­hydrogen-donor ligand 2,2'-bipyridine (bpy). We identified by NMR spectroscopy that [Co(bpy)3]3+ binds to the highly sulfated synthetic pentasaccharide, Fondaparinux (FPX), while no major perturbations are found in the presence of [Ru(bpy)3]2+. This result is of significance as both coordination compounds have analogous 3D structures. Although weakly binding to the model GAG, [Ru(bpy)3]2+ completely inhibits the enzymatic cleavage of FPX by the bacterial heparinase II (HepII) enzyme, which is not observed for the Co(III) analog. This observation suggests a direct inhibition of HepII by the Ru compound, through a mechanism that is unrelated to metalloshielding.


Assuntos
2,2'-Dipiridil/química , Cobalto/química , Complexos de Coordenação/química , Compostos de Rutênio/química , Fondaparinux/química , Glicosaminoglicanos/química , Humanos , Ligação de Hidrogênio , Ligantes , Espectroscopia de Ressonância Magnética/métodos , Compostos Organometálicos/química , Polissacarídeo-Liases/química , Rutênio/química
14.
Dalton Trans ; 51(10): 3937-3953, 2022 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-35171173

RESUMO

Ruthenium complexes are being studied extensively as anticancer drugs following the inclusion of NAMI-A and KP1019 in phase II clinical trials for the treatment of metastatic phase and primary tumors. Herein, we designed and synthesized four organometallic Ru(II)-arene complexes [Ru(η6-p-cymene)(L)Cl] (1), [Ru(η6-benzene)(L)Cl] (2), [Ru(η6-p-cymene)(L)N3] (3) and [Ru(η6-benzene)(L)N3] (4) [HL = (E)-N'-(pyren-1-ylmethylene)thiopene-2-carbohydrazide] that have anticancer, antimetastatic and two-photon cell imaging abilities. Moreover, in the transfer hydrogenation of NADH to NAD+, these compounds also display good catalytic activity. All the complexes, 1-4, are well characterized by spectroscopic techniques (NMR, mass, FTIR, UV-vis and fluorescence). The single crystal X-ray diffraction technique proved that the ligand L coordinates through an N,O-bidentate chelating fashion in the solid-state structures of complexes 1 and 2. The stability study of the complexes was performed through UV-visible spectroscopy. The cytotoxicities of all the complexes were screened through MTT assay and the results revealed that the complexes have potential anticancer activity against various cancerous cells (HeLa, MCF7 and A431). Studies with spectroscopic techniques revealed that complexes 1-4 exhibit strong interactions with biological molecules i.e. proteins (HSA and BSA) and CT-DNA. The density functional theory (DFT-D) method has been employed in the present study to know the interaction between DNA and complexes by calculating the HOMO and LUMO energy. A plausible mechanism for NADH oxidation has also been explored and the DFT calculations are found to be in accord with the experimental observation. Furthermore, we have investigated intracellular reactive oxygen species (ROS) generation capabilities in the MCF7 breast cancer cell line. The Hoechst/PI dual staining method confirmed the apoptosis mode of cell death. Meanwhile, complexes 1-4 show capabilities to prevent the metastasis phase of cancer cells by inhibiting cell migration.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Pirenos/química , Compostos de Rutênio/química , Compostos de Rutênio/farmacologia , Antineoplásicos/síntese química , Catálise , Linhagem Celular Tumoral , Sobrevivência Celular , Complexos de Coordenação , DNA/química , Humanos , Ligação Proteica , Compostos de Rutênio/síntese química , Análise de Célula Única
15.
Molecules ; 27(2)2022 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-35056783

RESUMO

To meet the demand for alternatives to commonly used antibiotics, this paper evaluates the antimicrobial potential of arene-ruthenium(II) complexes and their salts, which may be of value in antibacterial treatment. Their antimicrobial activity (MIC, MBC/MFC) was examined in vitro against Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Pseudomonas aeruginosa, Proteus vulgaris and Candida albicans and compared with classic antibiotics used as therapeutics. Selected arene-ruthenium(II) complexes were found to have synergistic effects with oxacillin and vancomycin against staphylococci. Their bactericidal effect was found to be associated with cell lysis and the ability to cut microbial DNA. To confirm the safety of the tested arene-ruthenium(II) complexes in vivo, their cytotoxicity was also investigated against normal human foreskin fibroblasts (HFF-1). In addition, the antioxidant and thus pro-health potential of the compounds, i.e., their nonenzymatic antioxidant capacity (NEAC), was determined by two different methods: ferric-TPTZ complex and DPPH assay.


Assuntos
Antibacterianos/farmacologia , Resistência Microbiana a Medicamentos/efeitos dos fármacos , Hidrocarbonetos Aromáticos/farmacologia , Pirazóis/farmacologia , Compostos de Rutênio/farmacologia , Antibacterianos/química , Antioxidantes/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Sinergismo Farmacológico , Fibroblastos/efeitos dos fármacos , Prepúcio do Pênis/citologia , Prepúcio do Pênis/efeitos dos fármacos , Sequestradores de Radicais Livres/farmacologia , Humanos , Hidrocarbonetos Aromáticos/química , Masculino , Oxacilina/farmacologia , Pirazóis/química , Compostos de Rutênio/química , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus epidermidis/efeitos dos fármacos , Vancomicina/farmacologia
16.
Dalton Trans ; 51(4): 1489-1501, 2022 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-34989381

RESUMO

We have synthesized and characterized three new ruthenium(II) diphosphine complexes containing an acylthiourea ligand, with the general formula [Ru(DPEPhos)(O,S)(bipy)]PF6, where DPEPhos = bis(2-(diphenylphosphino)phenyl)ether, bipy = 2,2'-bipyridine, and O,S = N,N-dimethyl-N'-(benzoyl)thiourea (1), N,N-dimethyl-N'-(furoyl)thiourea (2), and N,N-dimethyl-N'-(thiophenyl)thiourea (3), by several physicochemical techniques. We evaluated the ruthenium complexes for their cytotoxicity against two human cancer cell lines, A549 (lung) and MDA-MB-231 (breast), and two corresponding lines of non-cancer cells, MRC-5 (lung) and MCF-10A (breast). All the complexes are cytotoxic against the cancer cell lines; the IC50 values lie in the micromolar range (0.07-0.70 µM). Ruthenium complex 1 is more selective (7 times more active) toward lung cancer cells (A549) than toward non-cancer cells (MRC-5) and is 160 times more cytotoxic than cisplatin against A549 cells. Investigations of the mechanism of action of complex 1 in A549 cells demonstrated that it inhibits colony formation and promotes cell cycle arrest in the G1 phase and apoptotic cell death. DNA binding studies revealed that complexes 1-3 interact with the biomolecule via minor grooves. These complexes also interact with human serum albumin (HSA) and have affinity for site I by hydrophobic forces. Therefore, this new class of ruthenium complexes can act as cytotoxic agents, mainly for lung cancer treatment.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Complexos de Coordenação/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Compostos de Rutênio/farmacologia , Tioureia/análogos & derivados , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/uso terapêutico , Feminino , Humanos , Compostos de Rutênio/síntese química , Compostos de Rutênio/uso terapêutico , Tioureia/química
17.
Dalton Trans ; 51(4): 1333-1343, 2022 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-34989734

RESUMO

Three ruthenium(III) complexes with pyrazolopyrimidine [Ru(Ln)(H2O)Cl3] (1-3, n = 1-3) were prepared and characterized. These Ru(III) compounds show strong cytotoxicity against six cancer cell lines and low toxicity to normal human liver cells. Particularly, they exhibited stronger cytotoxicity to SK-OV-3 cells than cisplatin. Mechanism studies revealed that complex 1 inhibited tumor cell invasion and suppressed cell proliferation, induced apoptosis by elevating the levels of intracellular ROS (reactive oxygen species) and free calcium (Ca2+), and reduced mitochondrial membrane potential (ΔΨ). It also activated the caspase cascade, accompanied with upregulation of cytochrome c, Bax, p53, Apaf-1 and downregulation of Bcl-2. Moreover, complex 1 caused cell cycle arrest at S phase by inhibiting the expression of CDC 25, cyclin A2 and CDK 2 proteins, and induced DNA damage by interacting with DNA and inhibiting the topoisomerase I enzyme. Complex 1 exhibited efficient in vivo anticancer activity in a model of SK-OV-3 tumor xenograft.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/uso terapêutico , Piridinas/uso terapêutico , Compostos de Rutênio/uso terapêutico , Animais , Antineoplásicos/química , Apoptose , Benzimidazóis , Cálcio , Caspase 3/genética , Caspase 3/metabolismo , Caspase 9/genética , Caspase 9/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , Dano ao DNA , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Membranas Mitocondriais/efeitos dos fármacos , Piridinas/química , Espécies Reativas de Oxigênio , Compostos de Rutênio/química , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Dalton Trans ; 51(5): 1888-1900, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-35018930

RESUMO

The purpose of this study was to investigate the correlation between the spectroscopic and photophysical properties of Ru(II) polypyridyl complexes and their photodynamic activity in vitro. A series of Ru(II) polypyridyl complexes with 4,7-diphenyl-1,10-phenanthroline (dip) and 2,3-bis(2-pyridyl)quinoxaline (dpq) and its derivatives were synthesized and characterized regarding their photophysical, biological, and photodynamic properties. The complexes were evaluated not only in the context of 1O2 generation but also regarding other types of reactive oxygen species (ROS) to assess the possibility of Ru(II) complexes to induce phototoxicity via various ROS using fluorescence and EPR spectroscopy. The compounds were found to be moderately cytotoxic with IC50 values ranging from 1 to 35 µM and retained their cytotoxic activity under hypoxic conditions. The unraveled phototoxic activity is based mainly on the generation of H2O2 and 1O2, highlighting the importance of electron-transfer processes in the observed photodynamic activity of Ru polypyridyl complexes. A combination of photodynamic activity with cytotoxicity under decreased dioxygen concentrations may help overcome the current photodynamic therapy (PDT) limitation. The findings highlight the need for broadening the scope of tested Ru-based photosensitizers.


Assuntos
Transporte de Elétrons/fisiologia , Oxigênio/metabolismo , Fenantrolinas/química , Compostos de Rutênio/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular , Sistema Livre de Células , Humanos , Peróxido de Hidrogênio , Camundongos , Modelos Moleculares , Estrutura Molecular , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Espécies Reativas de Oxigênio , Compostos de Rutênio/química
19.
Photochem Photobiol ; 98(1): 102-116, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34411308

RESUMO

We report new ruthenium complexes bearing the lipophilic bathophenanthroline (BPhen) ligand and dihydroxybipyridine (dhbp) ligands which differ in the placement of the OH groups ([(BPhen)2 Ru(n,n'-dhbp)]Cl2 with n = 6 and 4 in 1A and 2A , respectively). Full characterization data are reported for 1A and 2A and single crystal X-ray diffraction for 1A . Both 1A and 2A are diprotic acids. We have studied 1A , 1B , 2A , and 2B (B = deprotonated forms) by UV-vis spectroscopy and 1 photodissociates, but 2 is light stable. Luminescence studies reveal that the basic forms have lower energy 3 MLCT states relative to the acidic forms. Complexes 1A and 2A produce singlet oxygen with quantum yields of 0.05 and 0.68, respectively, in acetonitrile. Complexes 1 and 2 are both photocytotoxic toward breast cancer cells, with complex 2 showing EC50 light values as low as 0.50 µM with PI values as high as >200 vs. MCF7. Computational studies were used to predict the energies of the 3 MLCT and 3 MC states. An inaccessible 3 MC state for 2B suggests a rationale for why photodissociation does not occur with the 4,4'-dhbp ligand. Low dark toxicity combined with an accessible 3 MLCT state for 1 O2 generation explains the excellent photocytotoxicity of 2.


Assuntos
Neoplasias da Mama , Rutênio , Feminino , Humanos , Ligantes , Fenantrolinas , Rutênio/química , Compostos de Rutênio
20.
J Pharmacol Exp Ther ; 380(1): 47-53, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34728560

RESUMO

Ruthenium compounds, nitric oxide donors in biologic systems, have emerged as a promising therapeutic alternative to conventional drugs in anticancer chemotherapy and as a potential neuroprotective agent with fewer cytotoxic effects. This minireview summarizes promising studies with ruthenium complexes and their roles in cancer, neuroinflammation, neurovascular, and neurodegenerative diseases. The up-to-date evidence supports that ruthenium-based compounds have beneficial effects against gliomas and other types of brain cancers, reduce motor symptoms in models of cerebral ischemia-reperfusion, and may act in the control of nociceptive and inflammatory events, such as those seen in early Alzheimer's disease. More studies are needed to fill many current knowledge gaps about the intricate and complex biologic effects and therapeutic-related mechanisms of ruthenium, stimulating further research. SIGNIFICANCE STATEMENT: This minireview summarizes studies addressing the role of ruthenium compounds on neurological illnesses, focusing on brain cancer and neurovascular and neurodegenerative diseases. No such review is available in the literature.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Doadores de Óxido Nítrico/uso terapêutico , Compostos de Rutênio/uso terapêutico , Animais , Neoplasias Encefálicas/metabolismo , Humanos , Doenças Neurodegenerativas/metabolismo
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