RESUMO
Metallocompounds have emerged as promising new anticancer agents, which can also exhibit properties to be used in photodynamic therapy. Here, we prepared two ruthenium-based compounds with a 2,2'-bipyridine ligand conjugated to an anthracenyl moiety. These compounds coded GRBA and GRPA contain 2,2'-bipyridine or 1,10-phenathroline as auxiliary ligands, respectively, which provide quite a distinct behavior. Notably, compound GRPA exhibited remarkably high photoproduction of singlet oxygen even in water (ÏΔ = 0.96), almost twice that of GRBA (ÏΔ = 0.52). On the other hand, this latter produced twice more superoxide and hydroxyl radical species than GRPA, which may be due to the modulation of their excited state. Interestingly, GRPA exhibited a modest binding to DNA (Kb = 4.51 × 104), while GRBA did not show a measurable interaction only noticed by circular dichroism measurements. Studies with bacteria showed a great antimicrobial effect, including a synergistic effect in combination with commercial antibiotics. Besides that, GRBA showed very low or no cytotoxicity against four mammalian cells, including a hard-to-treat MDA-MB-231, triple-negative human breast cancer. Potent activities were measured for GRBA upon blue light irradiation, where IC50 of 43 and 13 nmol L-1 were seen against hard-to-treat triple-negative human breast cancer (MDA-MB-231) and ovarian cancer cells (A2780), respectively. These promising results are an interesting case of a simple modification with expressive enhancement of biological activity that deserves further biological studies.
Assuntos
Antibacterianos , Antineoplásicos , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Estrutura Molecular , Testes de Sensibilidade Microbiana , Ensaios de Seleção de Medicamentos Antitumorais , Compostos de Rutênio/farmacologia , Compostos de Rutênio/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Linhagem Celular Tumoral , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/síntese química , Rutênio/química , Rutênio/farmacologia , Proliferação de Células/efeitos dos fármacos , Farmacorresistência Bacteriana/efeitos dos fármacos , Processos Fotoquímicos , Sobrevivência Celular/efeitos dos fármacos , FotoquimioterapiaRESUMO
The bacterial infection and poor osseointegration of Ti implants could significantly compromise their applications in bone repair and replacement. Based on the carrier separation ability of the heterojunction and the redox reaction of pseudocapacitive metal oxides, we report an electrically responsive TiO2-SnO2-RuO2 coating with a multilayered heterostructure on a Ti implant. Owing to the band gap structure of the TiO2-SnO2-RuO2 coating, electron carriers are easily enriched at the coating surface, enabling a response to the endogenous electrical stimulation of the bone. With the formation of SnO2-RuO2 pseudocapacitance on the modified surface, the postcharging mode can significantly change the surface chemical state of the coating due to the redox reaction, enhancing the antibacterial ability and osteogenesis-related gene expression of the human bone marrow mesenchymal stem cells. Owing to the attraction for Ca2+, only the negatively postcharged SnO2@RuO2 can promote apatite deposition. The in vivo experiment reveals that the S-SnO2@RuO2-NP could effectively kill the bacteria colonized on the surface and promote osseointegration with the synostosis bonding interface. Thus, negatively charging the electrically responsive coating of TiO2-SnO2-RuO2 is a good strategy to endow modified Ti implants with excellent antibacterial ability and osseointegration.
Assuntos
Antibacterianos , Materiais Revestidos Biocompatíveis , Osseointegração , Compostos de Estanho , Titânio , Titânio/química , Titânio/farmacologia , Osseointegração/efeitos dos fármacos , Antibacterianos/farmacologia , Antibacterianos/química , Humanos , Materiais Revestidos Biocompatíveis/química , Materiais Revestidos Biocompatíveis/farmacologia , Compostos de Estanho/química , Compostos de Estanho/farmacologia , Animais , Compostos de Rutênio/química , Compostos de Rutênio/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Propriedades de Superfície , Osteogênese/efeitos dos fármacosRESUMO
The phenomenon of ischemic postconditioning (PostC) is known to be neuroprotective against ischemic reperfusion (I/R) injury. One of the key processes in PostC is the opening of the mitochondrial ATP-dependent potassium (mito-KATP) channel and depolarization of the mitochondrial membrane, triggering the release of calcium ions from mitochondria through low-conductance opening of the mitochondrial permeability transition pore. Mitochondrial calcium uniporter (MCU) is known as a highly sensitive transporter for the uptake of Ca2+ present on the inner mitochondrial membrane. The MCU has attracted attention as a new target for treatment in diseases, such as neurodegenerative diseases, cancer, and ischemic stroke. We considered that the MCU may be involved in PostC and trigger its mechanisms. This research used the whole-cell patch-clamp technique on hippocampal CA1 pyramidal cells from C57BL mice and measured changes in spontaneous excitatory post-synaptic currents (sEPSCs), intracellular Ca2+ concentration, mitochondrial membrane potential, and N-methyl-D-aspartate receptor (NMDAR) currents under inhibition of MCU by ruthenium red 265 (Ru265) in PostC. Inhibition of MCU increased the occurrence of sEPSCs (p = 0.014), NMDAR currents (p < 0.001), intracellular Ca2+ concentration (p < 0.001), and dead cells (p < 0.001) significantly after reperfusion, reflecting removal of the neuroprotective effects in PostC. Moreover, mitochondrial depolarization in PostC with Ru265 was weakened, compared to PostC (p = 0.004). These results suggest that MCU affects mitochondrial depolarization in PostC to suppress NMDAR over-activation and prevent elevation of intracellular Ca2+ concentrations against I/R injury.
Assuntos
Lesões Encefálicas , Canais de Cálcio , Pós-Condicionamento Isquêmico , Compostos de Rutênio , Animais , Camundongos , Camundongos Endogâmicos C57BL , Receptores de N-Metil-D-Aspartato , Trifosfato de AdenosinaRESUMO
6-mercaptopurine (6-MP) as the effective anti-cancer drug was used for the treatment of Crohn's disease and acute lymphoblastic leukaemia, but the response to maintenance therapy was variable with individual differences. In order to control the dosage and decrease the side effects of 6-MP, a sensitive and stable assay was urgently needed for 6-MP monitoring. Herein, RuZn NPs with electrochemical oxidation property and oxidase-like activity was proposed for dual-mode 6-MP monitoring. Burr-like RuZn NPs were prepared and explored to not only exhibit an electrochemical oxidation signal at 0.78 V, but also displayed excellent oxidase-like performances. RuZn NPs were utilized for the dual-mode monitoring of 6-MP, attributing to the formation of Ru-SH covalent bonding. The colorimetric method showed good linearity from 10 µM to 5 mM with the limit of detection (LOD) of 300 nM, while the electrochemical method provided a higher sensitivity with the LOD of 37 nM in range from 100 nM to 200 µM. This work provided a new way for the fabrication of dual-functional nanotags with electroactivity and oxidase-like property, and opened a dual-mode approach for the 6-MP detection applications with complementary and satisfactory results.
Assuntos
Nanopartículas Metálicas , Compostos de Rutênio/química , Compostos de Zinco/química , Elétrons , Oxirredução , Nanopartículas Metálicas/química , Nanopartículas Metálicas/ultraestrutura , Antineoplásicos/químicaRESUMO
Our prior studies have illustrated that the uracil ruthenium(II) diimino complex, [Ru(H3ucp)Cl(PPh3)] (1) (H4ucp = 2,6-bis-((6-amino-1,3-dimethyluracilimino)methylene)pyridine) displayed high hypoglycemic effects in diet-induced diabetic rats. To rationalize the anti-diabetic effects of 1, three new derivatives have been prepared, cis-[Ru(bpy)2(urdp)]Cl2 (2) (urdp = 2,6-bis-((uracilimino)methylene)pyridine), trans-[RuCl2(PPh3)(urdp)] (3), and cis-[Ru(bpy)2(H4ucp)](PF6)2 (4). Various physicochemical techniques were utilized to characterize the structures of the novel ruthenium compounds. Prior to biomolecular interactions or in vitro studies, the stabilities of 1-4 were monitored in anhydrous DMSO, aqueous phosphate buffer containing 2% DMSO, and dichloromethane (DCM) via UV-Vis spectrophotometry. Time-dependent stability studies showed ligand exchange between DMSO nucleophiles and chloride co-ligands of 1 and 3, which was suppressed in the presence of an excess amount of chloride ions. In addition, the metal complexes 1 and 3 are stable in both DCM and an aqueous phosphate buffer containing 2% DMSO. In the case of compounds 2 and 4 with no chloride co-ligands within their coordination spheres, high stability in aqueous phosphate buffer containing 2% DMSO was observed. Fluorescence emission titrations of the individual ruthenium compounds with bovine serum albumin (BSA) showed that the metal compounds interact non-discriminately within the protein's hydrophobic cavities as moderate to strong binders. The metal complexes were capable of disintegrating mature amylin amyloid fibrils. In vivo glucose metabolism studies in liver (Chang) cell lines confirmed enhanced glucose metabolism as evidenced by the increased glucose utilization and glycogen synthesis in liver cell lines in the presence of complexes 2-4.
Assuntos
Antineoplásicos , Complexos de Coordenação , Diabetes Mellitus Experimental , Rutênio , Ratos , Animais , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Soroalbumina Bovina/química , Rutênio/química , Dimetil Sulfóxido , Hipoglicemiantes/farmacologia , Cloretos , Diabetes Mellitus Experimental/tratamento farmacológico , Piridinas/química , Peptídeos , Compostos de Rutênio , Glucose , Fosfatos , Antineoplásicos/farmacologia , LigantesRESUMO
The successful choice of hit compounds during drug development programs involves the integration of structure-activity relationship (SAR) studies with pharmacokinetic determinations, including metabolic stability assays and metabolite profiling. A panel of nine ruthenium-cyclopentadienyl (RuCp) compounds with the general formula [Ru(η5-C5H4R)(PPh3)(bipyR')]+ (with R = H, CHO, CH2OH; R' = H, CH3, CH2OH, CH2Biotin) has been tested against hormone-dependent MCF-7 and triple negative MDA-MB-231 breast cancer cells. In general, all compounds showed important cytotoxicity against both cancer cell lines and were able to inhibit the formation of MDA-MB-231 colonies in a dose-dependent manner, while showing selectivity for cancer cells over normal fibroblasts. Among them, four compounds stood out as lead structures to be further studied. Cell distribution assays revealed their preference for the accumulation at cell membrane (Ru quantification by ICP-MS) and the mechanism of cell death seemed to be mediated by apoptosis. Potential structural liabilities of lead compounds were subsequently flagged upon in vitro metabolic stability assays and metabolite profiling. The implementation of this integrated strategy led to the selection of RT151 as a promising hit compound.
Assuntos
Antineoplásicos , Neoplasias da Mama , Complexos de Coordenação , Rutênio , Humanos , Feminino , Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Rutênio/química , Compostos de Rutênio/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Complexos de Coordenação/químicaRESUMO
Photodynamic therapy (PDT), as a new type of light-mediated reactive oxygen species (ROS) cancer therapy, has the advantages of high therapeutic efficiency, non-resistance, and less trauma than traditional cancer therapy such as surgery, radiotherapy, and chemotherapy. However, oxygen-dependent PDT further exacerbates tumor metastasis. To this end, a strategy that circumvents tumor metastasis to improve the therapeutic efficacy of PDT is proposed. Herein, a near-infrared light-activated photosensitive polymer is synthesized and branched the anti-metastatic ruthenium complex NAMI-A on the side, which is further assembled to form nanoparticles (NP2) for breast cancer therapy. NP2 can kill tumor cells by generating ROS under 808 nm radiation (NP2 + L), reduce the expression of matrix metalloproteinases (MMP2/9) in cancer cells, decrease the invasive and migration capacity of cancer cells, and eliminate cancer cells. Further animal experiments show that NP2 + L can inhibit tumor growth and reduce liver and lung metastases. In addition, NP2 + L can activate the immune system in mice to avoid tumor recurrence. In conclusion, a PDT capable of both preventing tumor metastasis and precisely hitting the primary tumor to achieve effective treatment of highly metastatic cancers is developed.
Assuntos
Dimetil Sulfóxido/análogos & derivados , Nanopartículas , Compostos Organometálicos , Fotoquimioterapia , Compostos de Rutênio , Animais , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Recidiva Local de Neoplasia/tratamento farmacológico , Nanopartículas/uso terapêutico , Polímeros , Linhagem Celular Tumoral , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêuticoRESUMO
The search for more effective and selective drugs to overcome cancer multidrug resistance is urgent. As such, a new series of ruthenium-cyclopentadienyl ("RuCp") compounds with the general formula [Ru(η5-C5H4R)(4,4'-R'-2,2'-bipy)(PPh3)] were prepared and fully characterized. All compounds were evaluated toward non-small cell lung cancer cells with different degrees of cisplatin sensitivity (A549, NCI-H2228, Calu-3, and NCI-H1975), showing better cytotoxicity than the first-line chemotherapeutic drug cisplatin. Compounds 2 and 3 (R' = -OCH3; R = CHO (2) or CH2OH (3)) further inhibited the activity of P-gp and MRP1 efflux pumps by impairing their catalytic activity. Molecular docking calculations identified the R-site P-gp pocket as the preferred one, which was further validated using site-directed mutagenesis experiments in P-gp. Altogether, our results unveil the first direct evidence of the interaction between P-gp and "RuCp" compounds in the modulation of P-gp activity and establish them as valuable candidates to circumvent cancer MDR.
Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Rutênio , Humanos , Antineoplásicos/farmacologia , Rutênio/farmacologia , Cisplatino/farmacologia , Simulação de Acoplamento Molecular , Compostos de Rutênio/farmacologia , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos AntineoplásicosRESUMO
Organoruthenium pyrithione (1-hydroxypyridine-2-thione) complexes have been shown in our recent studies to be a promising family of compounds for development of new anticancer drugs. The complex [(η6-p-cymene)Ru(pyrithionato)(pta)]PF6 contains phosphine ligand pta (1,3,5-triaza-7-phosphaadamantane) as a functionality that improves the stability of the complex and its aqueous solubility. Here, we report our efforts to find pta alternatives and discover new structural elements to improve the biological properties of ruthenium anticancer drugs. The pta ligand was replaced by a selection of phosphine, phosphite, and arsine ligands to identify new functionalities, leading to improvement in inhibitory potency towards enzyme glutathione S-transferase. In addition, cytotoxicity in breast, bone, and colon cancers was investigated.
Assuntos
Antineoplásicos , Complexos de Coordenação , Compostos Organometálicos , Fosfinas , Rutênio , Rutênio/farmacologia , Rutênio/química , Compostos de Rutênio , Antineoplásicos/farmacologia , Antineoplásicos/química , Compostos Organometálicos/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Linhagem Celular TumoralRESUMO
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/metabolismoRESUMO
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 BovinaRESUMO
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-LactamasesRESUMO
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/metabolismoRESUMO
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 RutênioRESUMO
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/químicaRESUMO
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 0.5â¯pg/mL to 500â¯ng/mL with a detection limit of 0.2â¯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 VascularRESUMO
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 FourierRESUMO
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 , Alicerces Teciduais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Celulose/química , Celulose/farmacologia , Glicina/farmacologia , Neurônios , Porosidade , Espectroscopia de Infravermelho com Transformada de Fourier , Engenharia Tecidual , Alicerces Teciduais/químicaRESUMO
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/químicaRESUMO
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.