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1.
Int J Mol Sci ; 22(19)2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34639127

RESUMO

Toxoplasma gondii is an apicomplexan parasite that infects and proliferates within many different types of host cells and infects virtually all warm-blooded animals and humans. Trypanosoma brucei is an extracellular kinetoplastid that causes human African trypanosomiasis and Nagana disease in cattle, primarily in rural sub-Saharan Africa. Current treatments against both parasites have limitations, e.g., suboptimal efficacy and adverse side effects. Here, we investigate the potential cellular and molecular targets of a trithiolato-bridged arene ruthenium complex conjugated to 9-(2-hydroxyethyl)-adenine (1), which inhibits both parasites with IC50s below 10-7 M. Proteins that bind to 1 were identified using differential affinity chromatography (DAC) followed by shotgun-mass spectrometry. A trithiolato-bridged ruthenium complex decorated with hypoxanthine (2) and 2-hydroxyethyl-adenine (3) were included as controls. Transmission electron microscopy (TEM) revealed distinct ultrastructural modifications in the mitochondrion induced by (1) but not by (2) and (3) in both species. DAC revealed 128 proteins in T. gondii and 46 proteins in T. brucei specifically binding to 1 but not 2 or 3. In T. gondii, the most abundant was a protein with unknown function annotated as YOU2. This protein is a homolog to the human mitochondrial inner membrane translocase subunit Tim10. In T. brucei, the most abundant proteins binding specifically to 1 were mitochondrial ATP-synthase subunits. Exposure of T. brucei bloodstream forms to 1 resulted in rapid breakdown of the ATP-synthase complex. Moreover, both datasets contained proteins involved in key steps of metabolism and nucleic acid binding proteins.


Assuntos
Nucleotídeos/química , Compostos de Rutênio/farmacologia , Compostos de Sulfidrila/química , Toxoplasma/efeitos dos fármacos , Toxoplasmose/tratamento farmacológico , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomíase/tratamento farmacológico , Humanos , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/metabolismo , Proteínas de Protozoários/metabolismo , Compostos de Rutênio/química , Toxoplasma/metabolismo , Toxoplasmose/metabolismo , Toxoplasmose/parasitologia , Trypanosoma brucei brucei/metabolismo , Tripanossomíase/metabolismo , Tripanossomíase/parasitologia
2.
Int J Mol Sci ; 22(19)2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34638791

RESUMO

Ruthenium complexes are developed as substitutes for platinum complexes to be used in the chemotherapy of hematological and gynecological malignancies, such as ovarian cancer. We synthesized and screened 14 ruthenium half-sandwich complexes with bidentate monosaccharide ligands in ovarian cancer cell models. Four complexes were cytostatic, but not cytotoxic on A2780 and ID8 cells. The IC50 values were in the low micromolar range (the best being 0.87 µM) and were similar to or lower than those of the clinically available platinum complexes. The active complexes were cytostatic in cell models of glioblastoma, breast cancer, and pancreatic adenocarcinoma, while they were not cytostatic on non-transformed human skin fibroblasts. The bioactive ruthenium complexes showed cooperative binding to yet unidentified cellular target(s), and their activity was dependent on reactive oxygen species production. Large hydrophobic protective groups on the hydroxyl groups of the sugar moiety were needed for biological activity. The cytostatic activity of the ruthenium complexes was dependent on reactive species production. Rucaparib, a PARP inhibitor, potentiated the effects of ruthenium complexes.


Assuntos
Neoplasias/tratamento farmacológico , Compostos de Rutênio/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Complexos de Coordenação , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Indóis/farmacologia , Indóis/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Espécies Reativas de Oxigênio , Compostos de Rutênio/síntese química , Compostos de Rutênio/química , Compostos de Rutênio/uso terapêutico
3.
Int J Mol Sci ; 22(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34445620

RESUMO

The clinical success of cisplatin, carboplatin, and oxaliplatin has sparked the interest of medicinal inorganic chemistry to synthesize and study compounds with non-platinum metal centers. Despite Ru(II)-polypyridyl complexes being widely studied and well established for their antitumor properties, there are not enough in vivo studies to establish the potentiality of this type of compound. Therefore, we report to the best of our knowledge the first in vivo study of Ru(II)-polypyridyl complexes against breast cancer with promising results. In order to conduct our study, we used MCF7 zebrafish xenografts and ruthenium complexes [Ru(bipy)2(C12H8N6-N,N)][CF3SO3]2Ru1 and [{Ru(bipy)2}2(µ-C12H8N6-N,N)][CF3SO3]4Ru2, which were recently developed by our group. Ru1 and Ru2 reduced the tumor size by an average of 30% without causing significant signs of lethality when administered at low doses of 1.25 mg·L-1. Moreover, the in vitro selectivity results were confirmed in vivo against MCF7 breast cancer cells. Surprisingly, this work suggests that both the mono- and the dinuclear Ru(II)-polypyridyl compounds have in vivo potential against breast cancer, since there were no significant differences between both treatments, highlighting Ru1 and Ru2 as promising chemotherapy agents in breast cancer therapy.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Compostos de Rutênio/química , Compostos de Rutênio/farmacologia , Animais , Apoptose , Neoplasias da Mama/patologia , Proliferação de Células , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Técnicas In Vitro , Estrutura Molecular , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
4.
Molecules ; 26(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34361697

RESUMO

Flavonoids are a class of natural polyphenolic compounds sharing a common 2-phenyl-3,4-dihydro-2H-1-benzopyran (flavan) backbone. Typically known for their antioxidant activity, flavonoids are also being investigated regarding antitumour and antimicrobial properties. In this review, we report on the complexation of both natural and synthetic flavonoids with ruthenium as a strategy to modulate the biological activity. The ruthenoflavonoid complexes are divided into three subclasses, according to their most prominent bioactivity: antitumour, antimicrobial, and protection of the cardiovascular system. Whenever possible the activity of the ruthenoflavonoids is compared with that of commercial drugs for a critical assessment of the feasibility of using them in future clinical applications.


Assuntos
Anti-Infecciosos/química , Antineoplásicos/química , Cardiotônicos/química , Fibrinolíticos/química , Flavonoides/química , Compostos Organometálicos/química , Compostos de Rutênio/química , Animais , Humanos , Camundongos
5.
J Colloid Interface Sci ; 603: 615-632, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34225068

RESUMO

Antibiotic resistanceand biofilm formation are the main challenges of bacterial infectious diseases, and enhancing the permeability of drugs to biofilms may be a promising strategy. Herein, we constructed a cationic chitosan coated ruthenium dioxide nanozyme (QCS-RuO2@RBT, SRT NSs)。RuO2 nanosheets (RuO2 NSs) are modified with positively charged Quaternary ammonium-chitosan (QCS) to improve biocompatibility, and enhance the interaction between RuO2 nanozymes and bacterial membranes. An antibacterial drug, [Ru(bpy)2(tip)]2+ (RBT) can be loaded onto QCS-RuO2 by π-π stacking and hydrophobic interaction. SRT NSs exhibit NIR light enhanced peroxidase-like catalytic activity, thereby effectively fighting against planktonic bacteria and damaging biofilms. In the biofilm, extracellular DNA (eDNA) was cleaved by high levels of hydroxyl radicals (•OH) catalyzed by SRT NSs, thereby disrupting the rigid biofilm. In addition, in vivo studies demonstrate that SRT NSs can significantly rescue skin wound infections and the chronic lung infection in mice caused by P. aeruginosa, and hold the same therapeutic efficacy as first-line clinically anchored anti P. aeruginosa drug ciprofloxacin. Accordingly, the research work has realized the efficient production of ·OH, and the permeability of drugs to biofilms.it provides a promising response strategy for the management of biofilm-associated infections, including chronic lung infection.


Assuntos
Infecções Bacterianas , Quitosana , Animais , Antibacterianos/farmacologia , Infecções Bacterianas/tratamento farmacológico , Biofilmes , Camundongos , Testes de Sensibilidade Microbiana , Terapia Fototérmica , Espécies Reativas de Oxigênio , Compostos de Rutênio
6.
J Colloid Interface Sci ; 604: 208-220, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34265681

RESUMO

HYPOTHESIS: Dynamic Light Scattering (DLS) generated particle size distributions (PSD) of polymer-stabilized nanoparticles are dependent on the optimization parameters used to generate an inversion solution fit to the measured autocorrelation function. The accuracy of the DLS PSD average and polydispersity can be determined by comparing analyzed Transmission Electron Microscopy (TEM) images with the DLS results if the TEM measured sizes can be corrected for the thickness of the hydrated polymer corona that impacts particle hydrodynamics but is a collapsed, desiccated shell in the TEM images. EXPERIMENTS: Nanoparticles were prepared by Flash NanoPrecipitation with either poly(ethylene glycol) (PEG) or hydroxypropyl methylcellulose acetate succinate (HPMCAS) stabilizing polymers. Solvated nanoparticle size distributions were measured by DLS in aqueous media. The same nanoparticle dispersions were lyophilized onto TEM grids and stained by ruthenium tetroxide (RuO4) vapor to improve electron contrast. Desiccated particle size distributions were generated by measuring a minimum of 300 particle diameters in the stained TEM images. FINDINGS: Using our protocol for staining soft matter nanoparticles in TEM measurements, we have quantitatively analyzed the correlation between DLS and TEM generated PSDs. Average diameters disagree by the hydrated polymer corona thickness for each stabilizer due to the high-vacuum TEM environment, with 21.4 nm for PEG and 51.2 nm for HPMCAS. While corrected average diameter agrees within 10% for each technique, DLS consistently over-estimates the standard deviation of the PSD by 100% compared to the TEM measurement.


Assuntos
Nanopartículas , Polímeros , Microscopia Eletrônica de Transmissão , Tamanho da Partícula , Compostos de Rutênio
7.
Molecules ; 26(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200469

RESUMO

The photophysical and biological properties of two new phenanthroline-based ligand ruthenium complexes were investigated in detail. Their DNA interaction modes were determined to be the intercalation mode using spectra titration and viscosity measurements. Under irradiation, obvious photo-reduced DNA cleavages were observed in the two complexes via singlet oxygen generation. Furthermore, complex 2 showed higher DNA affinity, photocleavage activity, and singlet oxygen quantum yields than complex 1. The two complexes showed no toxicity towards tumor cells (HeLa, A549, and A375) in the dark. However, obvious photocytotoxicities were observed in the two complexes. Complex 2 exhibited large PIs (phototherapeutic indices) (ca. 400) towards HeLa cells. The study suggests that these complexes may act as DNA intercalators, DNA photocleavers, and photocytotoxic agents.


Assuntos
Clivagem do DNA/efeitos dos fármacos , DNA/efeitos dos fármacos , Fenantrolinas/farmacologia , Compostos de Rutênio/farmacologia , Células A549 , Linhagem Celular Tumoral , Células HeLa , Humanos , Substâncias Intercalantes/farmacologia , Ligantes , Compostos Organometálicos/farmacologia , Oxigênio Singlete/metabolismo
8.
Int J Mol Sci ; 22(14)2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34299199

RESUMO

Continuing our studies on the mechanisms underlying the cytotoxicity of potential drugs, we have described several aspects of the in vitro anticancer activity of ruthenium(II) and platinum(II) complexes with bioactive, synthetic aminoflavone ligands. We examined the mechanism of proapoptotic activity of cis-dichlorobis(3-imino-2-methoxyflavanone)ruthenium(II), cis-dichlorobis(3-imino-2-ethoxyflavanone)ruthenium(II), and trans-dichlorobis(3-aminoflavone)platinum(II). Cisplatin was used as a reference compound. The cytotoxicity was investigated by MTT assay. The mechanism of proapoptotic activity of the tested compounds was investigated by evaluation of caspase-8 activity, cytometric analysis of annexin-V positive cells, and mitochondrial potential loss measurement. The results showed that ruthenium compounds break partially or completely the cisplatin resistance by activating the caspase 8-dependent apoptosis pathway and loss of mitochondrial membrane potential. Platinum compounds also have a cytostatic effect, but their action requires more exposure time. Potential mechanisms underlying drug resistance in the two pairs of cancer cell lines were investigated: total glutathione content, P-glycoprotein activity, and differences in the activity of DNA repair induced by nucleotide excision. Results showed that cisplatin-resistant cells have elevated glutathione levels relative to sensitive cells. Moreover, they indicated the mechanisms enabling cells to avoid apoptosis caused by DNA damage. Pg-P activity has no effect on the development of cisplatin resistance in the cell lines described.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Flavonoides/farmacologia , Neoplasias/tratamento farmacológico , Compostos de Platina/farmacologia , Compostos de Rutênio/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Caspase 8/metabolismo , Cisplatino/farmacologia , Complexos de Coordenação/química , Resistencia a Medicamentos Antineoplásicos , Flavonoides/química , Humanos , Ligantes , Neoplasias/metabolismo , Neoplasias/patologia , Compostos de Platina/química , Compostos de Rutênio/química , Células Tumorais Cultivadas
9.
Molecules ; 26(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070457

RESUMO

Cisplatin and derivatives are highly effective in the treatment of a wide range of cancer types; however, these metallodrugs display low selectivity, leading to severe side effects. Additionally, their administration often results in the development of chemoresistance, which ultimately results in therapeutic failure. This scenario triggered the study of other transition metals with innovative pharmacological profiles as alternatives to platinum, ruthenium- (e.g., KP1339 and NAMI-A) and gold-based (e.g., Auranofin) complexes being among the most advanced in terms of clinical evaluation. Concerning the importance of improving the in vivo selectivity of metal complexes and the current relevance of ruthenium and gold metals, this review article aims to survey the main research efforts made in the past few years toward the design and biological evaluation of target-specific ruthenium and gold complexes. Herein, we give an overview of the inorganic and organometallic molecules conjugated to different biomolecules for targeting membrane proteins, namely cell adhesion molecules, G-protein coupled receptors, and growth factor receptors. Complexes that recognize the progesterone receptors or other targets involved in metabolic pathways such as glucose transporters are discussed as well. Finally, we describe some complexes aimed at recognizing cell organelles or compartments, mitochondria being the most explored. The few complexes addressing targeted gene therapy are also presented and discussed.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Compostos de Ouro/farmacologia , Compostos de Rutênio/farmacologia , Antineoplásicos/administração & dosagem , Moléculas de Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Complexos de Coordenação/administração & dosagem , Compostos de Ouro/administração & dosagem , Humanos , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Receptores de Fatores de Crescimento/efeitos dos fármacos , Compostos de Rutênio/administração & dosagem
10.
Inorg Chem ; 60(12): 8826-8837, 2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34060309

RESUMO

How to deliver nitric oxide (NO) to a physiological target and control its release quantitatively is a key issue for biomedical applications. Here, a water-soluble nitrosylruthenium complex, [(CH3)4N][RuCl3(5cqn)(NO)] (H5cqn = 5-chloro-8-quinoline), was synthesized, and its structure was confirmed with 1H NMR and X-ray crystal diffraction. Photoinduced NO release was investigated with time-resolved Fourier transform infrared and electron paramagnetic resonance (EPR) spectroscopies. The binding constant of the [RuCl3(5cqn)(NO)]- complex with human serum albumin (HSA) was determined by fluorescence spectroscopy, and the binding mode was identified by X-ray crystallography of the HSA and Ru-NO complex adduct. The crystal structure reveals that two molecules of the Ru-NO complex are located in the subdomain IB, which is one of the major drug binding regions of HSA. The chemical structures of the Ru complexes were [RuCl3(5cqn)(NO)]- and [RuCl3(Glycerin)NO]-, in which the electron densities for all ligands to Ru are unambiguously identified. EPR spin-trapping data showed that photoirradiation triggered NO radical generation from the HSA complex adduct. Moreover, the near-infrared image of exogenous NO from the nitrosylruthenium complex in living cells was observed using a NO-selective fluorescent probe. This study provides a strategy to design an appropriate delivery system to transport NO and metallodrugs in vivo for potential applications.


Assuntos
Complexos de Coordenação/metabolismo , Óxido Nítrico/metabolismo , Compostos de Rutênio/metabolismo , Albumina Sérica Humana/metabolismo , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cristalografia por Raios X , Corantes Fluorescentes/química , Células HeLa , Humanos , Modelos Moleculares , Estrutura Molecular , Óxido Nítrico/química , Imagem Óptica , Processos Fotoquímicos , Compostos de Rutênio/química , Albumina Sérica Humana/química , Células Tumorais Cultivadas
11.
Toxicol Appl Pharmacol ; 426: 115618, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34126112

RESUMO

WHO suggests that colon cancer incidences are rising steadily, propelling researchers to search for novel chemotherapeutic options. Metal-based chemotherapy is a potential forte to explore ruthenium-based complexes, exhibiting the capability to influence a variety of cellular targets. We discovered the chemotherapeutic effects of ruthenium-rifampicin complex on HT-29 and HCT-116 human colorectal cell lines and on a chemically developed murine colorectal cancer model. Complex was synthesized and characterized by analytical techniques and evaluation of antioxidant potential along with DNA binding capabilities. The complex minimizes cellular propagation and initiates apoptotic events in the colon cancer cell lines of HT-29 and HCT-116. The results of the in vivo study suggest that the complex has been successful in minimizing the wide spectrum of aberrant crypt foci and hyperplastic lesions, as well as encouraging elevated amounts of CAT, SOD and glutathione. Along with that, p53 could be modulated by the ruthenium-rifampicin complex to interfere with apoptosis in colon carcinoma, initiated by the intrinsic apoptotic trail facilitated through Bcl2 and Bax, thus controlling the Akt/mTOR/VEGF pathway coupled through the WNT/ß-catenin trail. Ruthenium-rifampicin chemotherapy could interrupt, retract or interrupt the progression of colorectal cancer through modifying intrinsic apoptosis including the antiangiogenic pathway, thereby achieving the function of a potential contender in chemotherapy in the near future.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Rifampina/uso terapêutico , Compostos de Rutênio/uso terapêutico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Colo/efeitos dos fármacos , Colo/patologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Combinação de Medicamentos , Feminino , Células HCT116 , Células HT29 , Humanos , Masculino , Camundongos Endogâmicos BALB C , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Wistar , Rifampina/farmacologia , Rifampina/toxicidade , Compostos de Rutênio/farmacologia , Compostos de Rutênio/toxicidade , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
12.
Top Curr Chem (Cham) ; 379(4): 29, 2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34109453

RESUMO

This review concentrates on recent developments in ruthenium Schiff bases, whose steric and electronic characteristics can be manipulated easily by selecting suitable condensing aldehydes or ketones and primary amines, and their metal complexes. Ruthenium metal-based complexes and Schiff base ligands are rapidly becoming conventionally considered for biological applications (antioxidant, anticancer, antimicrobial), in catalysis, in functional materials, in sensors, and as pigments for dyes. Ruthenium complexes exhibit a broad variety of activities concerning simple Schiff base ligands. This may be due to the octahedral bonding of both Ru(II) and Ru(III) complexes, which acquire an extended reservoir of a three-dimensional framework, providing the potential for an elevated degree of site selectivity for binding to their biological targets. This review provides an overview of this field, and intends to highlight both ligand design and synthetic methodology development, as well as significant applications of these metal complexes. In this review, we summarize our work on the development of ruthenium complexes, which was performed over the last few years.


Assuntos
Compostos de Rutênio/síntese química , Compostos de Rutênio/farmacologia , Bases de Schiff , Antibacterianos/síntese química , Antibacterianos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antioxidantes/síntese química , Antioxidantes/farmacologia , Desenho de Fármacos
13.
J Biol Inorg Chem ; 26(4): 385-401, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33837856

RESUMO

Metal complexes based on ruthenium have established excellent activity with less toxicity and great selectivity for tumor cells. This study aims to assess the anticancer potential of ruthenium(II)/allopurinol complexes called [RuCl2(allo)2(PPh3)2] (1) and [RuCl2(allo)2(dppb)] (2), where allo means allopurinol, PPh3 is triphenylphosphine and dppb, 1,4-bis(diphenylphosphino)butane. The complexes were synthesized and characterized by elemental analysis, IR, UV-Vis and NMR spectroscopies, cyclic voltammetry, molar conductance measurements, as well as the X-ray crystallographic analysis of complex 2. The antitumor effects of compounds were determined by cytotoxic activity and cellular and molecular responses to cell death mechanisms. Complex 2 showed good antitumor profile prospects because in addition to its cytotoxicity, it causes cell cycle arrest, induction of DNA damage, morphological and biochemical alterations in the cells. Moreover, complex 2 induces cell death by p53-mediated apoptosis, caspase activation, increased Beclin-1 levels and decreased ROS levels. Therefore, complex 2 can be considered a suitable compound in antitumor treatment due to its cytotoxic mechanism.


Assuntos
Alopurinol/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias Mamárias Animais/tratamento farmacológico , Compostos de Rutênio/química , Compostos de Rutênio/farmacologia , Alopurinol/química , Animais , Líquido Ascítico/citologia , Ciclo Celular/efeitos dos fármacos , Ensaios de Migração Celular , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Feminino , Fibroblastos , Humanos , Camundongos , Neoplasias Experimentais/tratamento farmacológico
14.
ACS Appl Mater Interfaces ; 13(17): 19572-19580, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33900720

RESUMO

Photoresponsive ruthenium (Ru) complexes have been extensively studied in the photodynamic therapy (PDT) of cancer. The metal-to-ligand charge transfer (MLCT) absorption maximum of most Ru complexes is located in the short-wavelength visible region, which is well suited for superficial tumors but shows inefficient therapeutic effects for more deep-seated ones. Moreover, Ru complexes are primarily located in the mitochondria or nucleus, always resulting in high levels of dark toxicity and DNA mutation. Herein, we reported a new ruthenium complex (Ru-I) for red-light-triggered PDT. The activation wavelength of Ru-I is successfully extended to 660 nm. Importantly, the complex photosensitizer can be quickly taken up by cancer cells and selectively accumulated in the lysosome, an ideal localization for PDT purposes. Intratumoral injection of Ru-I into tumor-bearing mice achieved excellent therapeutic effects and thus holds great promise for applications in lysosome localization photodynamic therapy.


Assuntos
Complexos de Coordenação/farmacologia , Luz , Lisossomos/metabolismo , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Compostos de Rutênio/farmacologia , Animais , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Fármacos Fotossensibilizantes/metabolismo , Compostos de Rutênio/metabolismo , Frações Subcelulares/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
15.
J Nutr Biochem ; 94: 108645, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33838230

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a chronic disease affecting the health of many people worldwide. Previous studies have shown that dietary calcium supplementation may alleviate NAFLD, but the underlying mechanism is not clear. In this study investigating the effect of calcium on hepatic lipid metabolism, 8-week-old male C57BL/6J mice were divided into four groups (n = 6): (1) mice given a normal chow containing 0.5% calcium (CN0.5), (2) mice given a normal chow containing 1.2% calcium (CN1.2), (3) mice given a high-fat diet (HFD) containing 0.5% calcium (HFD0.5), and (4) mice fed a HFD containing 1.2% calcium (HFD1.2). To understand the underlying mechanism, cells were treated with oleic acid and palmitic acid to mimic the HFD conditions in vitro. The results showed that calcium alleviated the increase in triglyceride accumulation induced by oleic acid and/or palmitic acid in HepG2, AML12, and primary hepatocyte cells. Our data demonstrated that calcium supplementation alleviated HFD-induced hepatic steatosis through increased liver lipase activity, proving calcium is involved in the regulation of hepatic lipid metabolism. Moreover, calcium also increased the level of glycogen in the liver, and at the same time had the effect of reducing glycolysis and promoting glucose absorption. Calcium addition increased calcium levels in the mitochondria and cytoplasm. Taken together, we concluded that calcium supplementation could relieve HFD-induced hepatic steatosis by changing energy metabolism and lipase activity.


Assuntos
Cálcio/administração & dosagem , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/tratamento farmacológico , Lipólise , Animais , Cálcio/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitoxantrona/farmacologia , Compostos de Rutênio/farmacologia
16.
Int J Mol Sci ; 22(9)2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33924780

RESUMO

Procoagulant snake venoms have been inhibited by the ruthenium containing compounds CORM-2 and RuCl3 separately, presumably by interacting with critical histidine or other sulfur-containing amino acids on key venom enzymes. However, combinations of these and other platinoid containing compounds could potentially increase, decrease or not affect the procoagulant enzyme function of venom. Thus, the purpose of this investigation was to determine if formulations of platinoid compounds could inhibit venom procoagulant activity and if the formulated compounds interacted to enhance inhibition. Using a human plasma coagulation kinetic model to assess venom activity, six diverse venoms were exposed to various combinations and concentrations of CORM-2, CORM-3, RuCl3 and carboplatin (a platinum containing compound), with changes in venom activity determined with thrombelastography. The combinations of CORM-2 or CORM-3 with RuCl3 were found to enhance inhibition significantly, but not in all venoms nor to the same extent. In sharp contrast, carboplatin-antagonized CORM-2 mediated the inhibition of venom activity. These preliminary results support the concept that platinoid compounds may inhibit venom enzymatic activity at the same or different molecular sites and may antagonize inhibition at the same or different sites. Further investigation is warranted to determine if platinoid formulations may serve as potential antivenoms.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Compostos Organometálicos/uso terapêutico , Compostos de Rutênio/uso terapêutico , Mordeduras de Serpentes/tratamento farmacológico , Carboplatina/farmacologia , Carboplatina/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Humanos , Compostos Organometálicos/farmacologia , Compostos de Rutênio/farmacologia , Venenos de Serpentes/farmacologia , Tromboelastografia
17.
Bioorg Chem ; 110: 104749, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33652341

RESUMO

Real-time monitoring of drug metabolism in vivo is of great significance to drug development and toxicology research. The purpose of this study is to establish a rapid and visual in vivo detection method for the detection of an intermediate metabolite of the gold (I) drug. Gold (I) drugs such as sodium aurothiomalate (AuTM) have anti-inflammatory effects in the treatment of rheumatoid arthritis. Gold(III) ions (Au3+) are the intermediate metabolite of gold medicine, and they are also the leading factor of side effects in the treatment of patients. However, the rapid reduction of Au3+ to Au+ by thiol proteins in organisms limits the in-depth study of metabolism of gold drugs in vivo. Here we describe a luminescence Au3+ probe (RA) based on ruthenium (II) complex for detecting Au3+ in vitro and in vivo. RA with large Stokes shift, good water solubility and biocompatibility was successfully applied to detect Au3+ in living cells and vivo by luminescence imaging, and to trap the fluctuation of Au3+ level produced by gold (I) medicine. More importantly, the luminescent probe was used to the detection of the intermediate metabolites of gold (I) drugs for the first time. Overall, this work offers a new detection tool/method for a deeper study of gold (I) drugs metabolite.


Assuntos
Corantes Fluorescentes/química , Tiomalato Sódico de Ouro/química , Tiomalato Sódico de Ouro/metabolismo , Ouro/química , Compostos de Rutênio/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Lipopolissacarídeos/toxicidade , Camundongos , Estrutura Molecular , Células RAW 264.7 , Análise de Célula Única , Peixe-Zebra
18.
Inorg Chem ; 60(4): 2138-2148, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33534562

RESUMO

Ruthenium complexes bearing protic diimine ligands are cytotoxic to certain cancer cells upon irradiation with blue light. Previously reported complexes of the type [(N,N)2Ru(6,6'-dhbp)]Cl2 with 6,6'-dhbp = 6,6'-dihydroxybipyridine and N,N = 2,2'-bipyridine (bipy) (1A), 1,10-phenanthroline (phen) (2A), and 2,3-dihydro-[1,4]dioxino[2,3-f][1,10]phenanthroline (dop) (3A) show EC50 values as low as 4 µM (for 3A) vs breast cancer cells upon blue light irradiation ( Inorg. Chem. 2017, 56, 7519). Herein, subscript A denotes the acidic form of the complex bearing OH groups, and B denotes the basic form bearing O- groups. This photocytotoxicity was originally attributed to photodissociation, but recent results suggest that singlet oxygen formation is a more plausible cause of photocytotoxicity. In particular, bulky methoxy substituents enhance photodissociation but these complexes are nontoxic ( Dalton Trans 2018, 47, 15685). Cellular studies are presented herein that show the formation of reactive oxygen species (ROS) and apoptosis indicators upon treatment of cells with complex 3A and blue light. Singlet oxygen sensor green (SOSG) shows the formation of 1O2 in cell culture for cells treated with 3A and blue light. At physiological pH, complexes 1A-3A are deprotonated to form 1B-3B in situ. Quantum yields for 1O2 (ϕΔ) are 0.87 and 0.48 for 2B and 3B, respectively, and these are an order of magnitude higher than the quantum yields for 2A and 3A. The values for Ï•Δ show an increase with 6,6'-dhbp derived substituents as follows: OMe < OH < O-. TD-DFT studies show that the presence of a low lying triplet metal-centered (3MC) state favors photodissociation and disfavors 1O2 formation for 2A and 3A (OH groups). However, upon deprotonation (O- groups), the 3MLCT state is accessible and can readily lead to 1O2 formation, but the dissociative 3MC state is energetically inaccessible. The changes to the energy of the 3MLCT state upon deprotonation have been confirmed by steady state luminescence experiments on 1A-3A and their basic analogs, 1B-3B. This energy landscape favors 1O2 formation for 2B and 3B and leads to enhanced toxicity for these complexes under physiological conditions. The ability to convert readily from OH to O- groups allowed us to investigate an electronic change that is not accompanied by steric changes in this fundamental study.


Assuntos
Antineoplásicos/química , Complexos de Coordenação/química , Luz , Processos Fotoquímicos , Compostos de Rutênio/química , Oxigênio Singlete/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Hipóxia Celular , Linhagem Celular Tumoral , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Prótons , Oxigênio Singlete/metabolismo , Espectrofotometria Ultravioleta
19.
Mitochondrion ; 57: 192-204, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33484870

RESUMO

Ru360, a mitochondrial Ca2+ uptake inhibitor, was tested in a unilateral fluid percussion TBI model in developing rats (P31). Vehicle and Ru360 treated TBI rats underwent sensorimotor behavioral monitoring between 24 and 72 h, thereafter which 185 brain metabolites were analyzed postmortem using LC/MS. Ru360 treatment after TBI improved sensorimotor behavioral recovery, upregulated glycolytic and pentose phosphate pathways, mitigated oxidative stress and prevented NAD+ depletion across both hemispheres. While neural viability improved ipsilaterally, it reduced contralaterally. Ru360 treatment, overall, had a global impact with most benefit near the strongest injury impact areas, while perturbing mitochondrial oxidative energetics in the milder TBI impact areas.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Metabolômica/métodos , Mitocôndrias/metabolismo , Compostos de Rutênio/administração & dosagem , Animais , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/psicologia , Cromatografia Líquida , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Masculino , Espectrometria de Massas , Via de Pentose Fosfato/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Compostos de Rutênio/farmacologia
20.
J Thromb Thrombolysis ; 51(3): 577-583, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33389608

RESUMO

In recent years a variety of metals (cadmium, chromium, copper, iron) have been demonstrated to modulate coagulation in vitro and in vivo. One group of metals, the platinoids, have not been assessed, and such investigation is justified given the thromboembolic phenomena associated with platinum-based chemotherapy. Thus, the goal of the present investigation was to assess the effects of carboplatin, cisplatin (platinum compounds), NAMI-A, and ruthenium chloride (ruthenium compounds) on human plasmatic coagulation. Human plasma was exposed to clinically relevant, equimolar concentrations of the aforementioned platinum and ruthenium compounds, with changes in plasmatic coagulation assessed via thrombelastography. The first series of experiments demonstrated no significant modulation of coagulation by the platinum compounds, while NAMI-A demonstrated mild hypercoagulability and ruthenium chloride exerted marked hypercoagulability. A second series of experiments utilizing a variety of specialized modifications of thrombelastography focused on ruthenium chloride revealed that this compound enhances prothrombin activation. While the hypercoagulability associated with platinum compounds in vivo do not appear to have a basis in plasmatic biochemistry, it appears that ruthenium compounds can exert procoagulant properties by enhancing the common pathway of human plasmatic coagulation. Future investigation of Ru based chemotherapeutic agents in development to assess procoagulant activity as part of evaluating their potential clinical safety is warranted.


Assuntos
Coagulação Sanguínea , Carboplatina/farmacologia , Cisplatino/farmacologia , Dimetil Sulfóxido/análogos & derivados , Compostos Organometálicos/farmacologia , Protrombina/metabolismo , Compostos de Rutênio/farmacologia , Tromboelastografia/métodos , Antineoplásicos/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Coagulação Sanguínea/fisiologia , Testes de Coagulação Sanguínea/métodos , Dimetil Sulfóxido/farmacologia , Humanos , Compostos de Platina/farmacologia , Trombofilia/sangue , Trombofilia/induzido quimicamente
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