RESUMO
Triphenylphosphine substitution reactions of [RuCl(PPh3)2(tpm)]Cl, 1, featuring tris(pyrazolyl)methane (tpm) as ligand, with the chlorambucil-decorated pyridine ligand PyCA, 3-aminopyridine (PyNH2) and 4-pyridinemethanol (PyOH) afforded the corresponding pyridine complexes 2-4 in high yields. PyCA was preliminarily obtained via esterification of 4-pyridinemethanol with chlorambucil. The new compounds PyCA and 2-3 were characterized by IR and multinuclear NMR spectroscopy. Additionally, the structure of 3 was ascertained by single crystal X-ray diffraction. The in vitro anti-proliferative activity of 2-4 and PyCA was determined against a panel of cancer cell lines, outlining 2 as the most performing compound. Targeted studies were subsequently undertaken using 2 to elucidate mechanistic aspects, including the assessment of ruthenium cellular uptake, cell cycle arrest, production of reactive oxygen species (ROS), western blotting and DNA damage (comet test). Overall, data highlight that the anticancer activity provided by 2 primarily affects the mitochondria pathway with a potential additional contribution from DNA damage.
Assuntos
Antineoplásicos , Proliferação de Células , Clorambucila , Complexos de Coordenação , Dano ao DNA , Rutênio , Humanos , Clorambucila/farmacologia , Clorambucila/química , Clorambucila/síntese química , Dano ao DNA/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Rutênio/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Ligantes , Pontos de Checagem do Ciclo Celular/efeitos dos fármacosRESUMO
Ruthenium(II) complexes (Ru1-Ru3) with the general formula [Ru(O-O)(PPh3)2(bipy)]PF6, bearing two triphenylphosphine (PPh3), bipyridine (bipy) and a series of natural and synthetic ß-diketones (O,O) ligands were synthesized and characterized using various analytical techniques. The interaction between the complexes and calf thymus DNA (CT-DNA) was investigated and demonstrated a weak interaction. The cytotoxicity of the complexes was investigated against breast cancer cells (MDA-MB-231 and MCF-7), lung cancer cells (A549), cisplatin-resistant ovarian cancer cells (A2780cis), as well as non-tumour lung (MRC-5) and non-tumour breast (MCF-10A) cell lines. All complexes exhibited cytotoxic activity against all the cell lines studied, with half maximal inhibitory concentration (IC50) values ranging from 0.39 to 13 µM. Notably, the three complexes demonstrated selectivity against the A2780cis cell line, with IC50 ranging from 0.39 to 0.82 µM. Among them, Ru2 exhibited the highest cytotoxicity, with an IC50 value of 0.39 µM. Consequently, this new class of complexes shows good selectivity towards cisplatin-resistant ovarian cancer cells and it is promising for further investigation as anti-cancer agents.
RESUMO
Reaction between the polymeric [RuCl2(CO)2]n and the N,N-bidentate ligand, 8-amino-quinoline (Quin), in methanol, afforded the photoactivated CO releasing molecule with the formula of trans-(Cl,Cl)-[RuCl2(CO)2Quin]. In the presence of biomolecules or in solvents with varying polarity and coordinating abilities, the solvatochromic characteristics and dark stability were investigated. A new board band emerged in the visible spectrum during the illumination, and its position varies according to the type of solvent used, indicating the role of the solvent in controlling the nature of the CO-depleted species. Spectral methods were used in combination with density functional theory simulations to get insight into the local minimum structure and the electronic properties of the Ru(II) complex. The results of the myoglobin assay showed that within the first two hours of illumination, one of the two CO molecules was released. The cytotoxic properties of the Ru(II)-based complex were investigated against normal mice bone marrow stromal cells and malignant human acute monocytic leukaemia cells.
Assuntos
Aminoquinolinas , Monóxido de Carbono , Complexos de Coordenação , Rutênio , Animais , Camundongos , Humanos , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Aminoquinolinas/química , Aminoquinolinas/farmacologia , Rutênio/química , Rutênio/farmacologia , Ligantes , Monóxido de Carbono/química , Mioglobina/química , Teoria da Densidade Funcional , LuzRESUMO
Pincer type coumarin based N-substituted semicarbazone ligands HL1-4 and their corresponding ruthenium(II) complexes (1-4) were synthesized, analyzed and confirmed by various spectro analytical techniques. The molecular structure of the ligand HL3 and complex 3 was confirmed by single crystal X-ray diffraction analysis. The stoichiometry of complexes 1, 2 and 4 was confirmed by high resolution mass spectroscopy (HRMS). The binding affinity of the compounds with CT-DNA (Calf Thymus DNA) and BSA (Bovine Serum Albumin) was established by absorption and emission titration methods. The results of In vitro cytotoxicity showed the significant cytotoxic potential of the complexes against MDA-MB-231 cells (TNBC- Triple-negative breast cancer). Among the complexes, 1 and 4 have shown appreciable results. Further, antimigratory activity against the MDA-MB-231 cells was studied for the complexes 1 and 4. The percentage cell cycle arrest, apoptosis and necrosis were explored by flow cytometry. The in vivo anti-tumor activity of the complexes 1 and 4 using C. elegans as model organism was established by using the tumoral C. elegans strain JK1466 (gld-1(q485)), which bears a mutation in the gld-1 tumor suppressor gene. We have determined the effect of our complexes on tumor gonad reduction and found to be non toxic to the JK1466 worms and they have prolonged their mean lifespan with potential antioxidant ability by overcoming stress responses. Overall, our study reported herein demonstrated that the complexes 1 and 4 could be established as potential metallo-drugs substantiating further exploration.
Assuntos
Antineoplásicos , Caenorhabditis elegans , Complexos de Coordenação , Rutênio , Humanos , Animais , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Rutênio/química , Rutênio/farmacologia , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Fatores de Transcrição Forkhead/metabolismo , Fatores de Transcrição Forkhead/genética , Longevidade/efeitos dos fármacos , Feminino , Células MDA-MB-231RESUMO
BACKGROUND: Rapid and sensitive detection for acetamiprid, a kind of widely used neonicotinoid insecticide, is very meaningful for the development of modern agriculture and the protection of human health. Highly stable electrochemiluminescence (ECL) materials are one of the key factors in ECL sensing technology. ECL materials prepared by porous materials (e.g., MOFs) coated with chromophores have been used for ECL sensing detection, but these materials have poor stability because the chromophores escape when they are in aqueous solution. Therefore, the development of highly stable ECL materials is of great significance to improve the sensitivity of ECL sensing technology. RESULTS: In this work, by combining etched metal-organic frameworks (E-UIO-66-NH2) as carrier with Tris(4,4'-dicarboxylic acid-2,2'-bipyridine)Ru(II) chloride (Ru(dcbpy)32+) as signal probe via amide bonds, highly stable nanocomposites (E-UIO-66-NH2-Ru) with excellent ECL performance were firstly prepared. Then, using MoS2 loaded with AuNPs as substrate material and co-reactant promoter, a signal off-on-off ECL aptamer sensor was prepared for sensitive detection of acetamiprid. Due to the excellent catalytic activity of E-UIO-66-NH2-Ru and MoS2@Au towards K2S2O8, the ECL signals can be enhanced by multiple signal enhancement pathways, the prepared ECL aptamer sensor could achieve sensitive detection of acetamiprid in the linear range of 10-13 to10-7 mol L-1, with the limit of detection (LOD) of 2.78â ¹10-15 mol L-1 (S/N = 3). After the evaluation of actual sample testing, this sensing platform was proven to be an effective method for the detection of acetamiprid in food and agricultural products. SIGNIFICANCE AND NOVELTY: The E-UIO-66-NH2-Ru prepared by linking Ru(dcbpy)32+ to E-UIO-66-NH2 via amide bonding has very high stability. The synergistic catalytic effect of MoS2 and AuNPs enhanced the ECL signal. By exploring the sensing mechanism and evaluating the actual sample tests, the proposed signal "on-off" ECL sensing strategy was proved to be an effective and excellent ECL sensing method for sensitive and stable detection of acetamiprid.
Assuntos
Aptâmeros de Nucleotídeos , Técnicas Eletroquímicas , Medições Luminescentes , Estruturas Metalorgânicas , Neonicotinoides , Neonicotinoides/análise , Técnicas Eletroquímicas/métodos , Aptâmeros de Nucleotídeos/química , Medições Luminescentes/métodos , Estruturas Metalorgânicas/química , Rutênio/química , Técnicas Biossensoriais/métodos , Limite de Detecção , Complexos de Coordenação/química , Inseticidas/análiseRESUMO
The potential use of Ru(II) complexes as photosensitizers (PSs) in photodynamic therapy (PDT) has gained significant attention. In comparison with fluorophores with aggregation-caused quenching (ACQ), fluorophores with aggregation-induced emission (AIE) characteristics exhibit sustained fluorescence and dispersibility in aqueous solutions. PSs with AIE characteristics have received much attention in recent years. Herein, we reported two novel biotin-conjugated Ru(II) polypyridyl complexes (Ru1 and Ru2) with AIE characteristics. When exposed to 460 nm (10 mW cm-2) light, Ru1 and Ru2 exhibited outstanding photostability and photocatalytic activity. Ru1 and Ru2 could efficiently generate singlet oxygen and induce pUC19 DNA photolysis when exposed to 460 nm light. Interestingly, both Ru1 and Ru2 also functioned as catalysts for NADH oxidation when exposed to 460 nm light. The presence of biotin fragments in Ru1 and Ru2 enhanced the specific uptake of these complexes by tumor cells. Both complexes showed minimal toxicity to selected cells in the dark. Nevertheless, the phototoxicity of both complexes significantly increased upon 460 nm light irradiation for 15 min. Further experiments revealed that Ru2 primarily accumulated in mitochondria and might bind to mitochondrial DNA. Under 460 nm light irradiation, Ru2 induced the generation of reactive oxygen species (ROS) and NADH depletion disrupting intracellular redox homeostasis in A549 cells, activating the mitochondrial apoptosis pathway resulting in up-regulation of apoptotic marker caspase-3, effectively damaged A549 cell DNA and arrested A549 cell cycle in the S phase. In vivo anti-tumor experiments were conducted to assess the effects of Ru2 on tumor growth in A549 tumor-bearing mice. The results showed that Ru2 effectively inhibited tumor growth under 460 nm light irradiation conditions. These findings indicate that Ru2 has great potential as a targeted photosensitizer for mitochondrial targeting imaging and photodynamic therapy of tumors.
Assuntos
Complexos de Coordenação , Fotoquimioterapia , Rutênio , Animais , Camundongos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/metabolismo , Biotina/farmacologia , Biotina/metabolismo , NAD/metabolismo , Fotoquimioterapia/métodos , Mitocôndrias/metabolismo , Oxirredução , DNA/metabolismo , Complexos de Coordenação/farmacologia , Complexos de Coordenação/metabolismo , Rutênio/farmacologiaRESUMO
Poor responses to medical care and the failure of pharmacological treatment for many high-frequency diseases, such as cancer and viral infections, have been widely documented. In this context, numerous metal-based substances, including cisplatin, auranofin, various gold metallodrugs, and ruthenium complexes, are under study as possible anticancer and antiviral agents. The two Ru(III) and Ru(II) complexes, namely, BOLD-100 and RAPTA-C, are presently being studied in a clinical trial and preclinical studies evaluation, respectively, as anticancer agents. Interestingly, BOLD-100 has also recently demonstrated antiviral activity against SARS-CoV-2, which is the virus responsible for the COVID-19 pandemic. Over the last years, much effort has been dedicated to discovering new dual anticancer-antiviral agents. Ru-based complexes could be very suitable in this respect. Thus, this review focuses on the most recent studies regarding newly synthesized Ru(II) complexes for use as anticancer and/or antiviral agents.
RESUMO
Background: The development of platinum-based metal complexes in oncology is limited due to vigorous toxicity and drug resistance. Objectives: This work aimed to study the cytotoxic activity and apoptosis induction of ruthenium complexes in a B16F10 cell line therapy. Methods: We prepared a series of innovative Ru(II) complexes [Ru(Tzphen)(bpy)(dcbpy)]+2 (S1), [Ru(dcbpy)2(Tzphen)]+2 (S2), [Ru(Phen)2(Tzphen)]+2 (S3), [Ru(Tzphen)(bpy)2]+2 (S4), [Ru(dmbpy)2(Tzphen)]+2 (S5) based on 1,10-phenanthroline ligand containing tetrazole and their anticancer properties investigated by cytotoxicity in vitro, reactive oxygen species, apoptosis with annexin V/PI staining method, autophagy, and cell uptake. Results: S1, S2, S3, S4, and S5 complexes showed comparable cytotoxicity activity relative to cisplatin against the B16F10 model. Moreover, intracellular ROS levels increased due to the presence of the complexes. Among the investigated complexes, the cells treated with the S5 complex indicated the highest apoptotic percentage (Q3) of 14.9% compared to the controls. The cell adsorption of the complexes also showed that the S4 and S5 complexes had higher cell adsorption, better internalization, and higher fluorescence light intensity. Conclusions: The present work provides important guidance for designing and using Ru complexes in cancer therapy.
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Light-activated treatments, such as photodynamic therapy (PDT), provide temporal and spatial control over a specific cytotoxic response by exploiting toxicity differences between irradiated and dark conditions. In this work, a novel strategy for developing near infrared (NIR)-activatable Ru(II) polypyridyl-based photosensitizers (PSs) was successfully developed through the incorporation of symmetric heptamethine cyanine dyes in the metal complex via a phenanthrimidazole ligand. Owing to their strong absorption in the NIR region, the PSs could be efficiently photoactivated with highly penetrating NIR light (770â nm), leading to high photocytotoxicities towards several cancer cell lines under both normoxic and hypoxic conditions. Notably, our lead PS (Ru-Cyn-1), which accumulated in the mitochondria, exhibited a good photocytotoxic activity under challenging low-oxygen concentration (2 % O2 ) upon NIR light irradiation conditions (770â nm), owing to a combination of type I and II PDT mechanisms. The fact that the PS Protoporphyrin IX (PpIX), the metabolite of the clinically approved 5-ALA PS, was found inactive under the same challenging conditions positions Ru-Cyn-1 complex as a promising PDT agent for the treatment of deep-seated hypoxic tumours.
Assuntos
Complexos de Coordenação , Neoplasias , Fotoquimioterapia , Rutênio , Humanos , Fármacos Fotossensibilizantes/farmacologia , Complexos de Coordenação/farmacologia , Corantes , Neoplasias/tratamento farmacológico , Rutênio/farmacologiaRESUMO
Two arene ruthenium(II) complexes [η6-(C6H6)Ru(pprip)Cl]PF6 (Ru1; pprip = 2-(3-phenyl-1H-pyrazol-4-yl)-imidazolo[4,5-f][1,10]phenanthroline) and [η6-(C6H6)Ru(H2iiP)Cl]PF6 (Ru2; H2iiP = 2-(indole-3-yl)-imidazolo[4,5-f][1,10]phenanthroline) have been synthesized and characterized in this work. Binding properties of Ru1 and Ru2 with the triplex RNA poly(U)â¢poly(A)*poly(U) were investigated by spectrophotometry and spectrofluorometry as well as viscosimetry. Analysis of spectroscopic titrations and viscosity measurements show that the two complexes bind with the triplex through intercalation, while the binding affinity for Ru2 toward the triplex is stronger than that for Ru1. Melting experiments indicate that the stabilizing effects of Ru1 and Ru2 toward the triplex differ from each other. Under the conditions used herein, Ru1 only stabilizes the Hoogsteen base-paired strand (third strand) without affecting stabilization of the Watson-Crick base-paired strand (the template duplex) of the triplex, while Ru2 stabilizes both the template duplex and the third strand. Although the two complexes prefer to stabilizing the third strand rather than the template duplex, the third-strand stabilization effect of Ru2 is stronger than that of Ru1. The obtained results of this work reveal that the planarity of the intercalative ligands plays an important role in the triplex stabilization by arene Ru(II) complexes.
Assuntos
Poli A , Rutênio , Poli A/química , Rutênio/química , Poli U/química , RNA/química , Fenantrolinas , Conformação de Ácido Nucleico , Espectrometria de FluorescênciaRESUMO
Two chiral ruthenium(II) polypyridyl complexes, Λ-[Ru(bpy)2(dppx)]2+ (bpy = 2,2'-bipyridine, dppx = 7,8-dimethyldipyridophenazine; Λ-1) and Δ-[Ru(bpy)2(dppx)]2+ (Δ-1) have been synthesized and characterized in this work. Interactions of Λ-1 and Δ-1 with the RNA triplex poly(U)â poly(A)*poly(U) have been investigated by various biophysical techniques. Spectrophotometric titrations and viscosity measurements suggested that enantiomers Λ-1 and Δ-1 bind with the triplex through intercalation, while the binding strengths of the two enantiomers toward the triplex differed only slightly from each other. Fluorescence titrations showed that although enantiomers Λ-1 and Δ-1 exhibited molecular "light switch" effects toward the triplex, the effect of Δ-1 was more marked. Furthermore, Furthermore, thermal denaturation showed that the two enantiomers have significantly different stabilizing effects on the triplex. The obtained results indicate that the racemic complex [Ru(bpy)2(dppx)]2+ is similar to a non-specific metallointercalator for the triplex investigated in this study, and chiralities of Ru(II) polypyridine complexes have an important influence on the binding and stabilizing effects of enantiomers toward the triplex. Two chiral ruthenium(II) polypyridyl complexes, Λ-[Ru(bpy)2(dppx)]2+ (bpy = 2,2'-bipyridine, dppx = 7,8-dimethyldipyridophenazine; Λ-1) and Δ-[Ru(bpy)2(dppx)]2+ (Δ-1) have been synthesized and characterized in this work. Interactions of Λ-1 and Δ-1 with the RNA triplex poly(U)â poly(A)*poly(U) have been investigated by various biophysical techniques. The obtained results indicate that the racemic complex [Ru(bpy)2(dppx)]2+ is similar as a non-specific metallointercalator for the triplex investigated in this study, and chiralities of Ru(II) polypyridine complexes have an important influence on the binding and stabilizing effects of enantiomers toward the triplex.
Assuntos
Poli A , Rutênio , Poli A/química , Rutênio/química , Poli U/química , 2,2'-Dipiridil , RNA/químicaRESUMO
Arene-ruthenium(II) complexes with carbothioamidopyrazoles at the C-2 and C-5 positions have been recognized as chemotherapeutic agent alternatives to cisplatin and its oxaliplatin analogs. The aim of this study was to continue research on the biological aspect of arene-ruthenium(II) complexes and their anticancer activity. The present paper includes an additional 12 new tumor cells, analyzed by MTT, and employs a series of extended bioassays to better understand their potential mechanism of antitumor activity. The following tests were conducted: membrane permeability studies, intramolecular reactive oxygen and nitrogen species (ROS/RNS) assays, mitochondrial potential changes, DNA analysis by comet assay using the electrophoresis method, measurement of cleaved PARP protein levels, and determination of apoptotic and necrotic cell fractions by fluorescence microscopy. Additionally, the article presents lipophilicity studies based on RP-TLC and molecular docking studies. We hope that the presented data will prove useful in practical treatment, especially for patients with cancer.
Assuntos
Antineoplásicos , Complexos de Coordenação , Neoplasias , Rutênio , Humanos , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Rutênio/farmacologia , Simulação de Acoplamento Molecular , Cisplatino , Espécies Reativas de Oxigênio/metabolismo , Complexos de Coordenação/farmacologia , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
Herein, two novel ruthenium(II) complexes coupled by erianin via a flexible carbon chain, [Ru(phen)2(L1-(CH2)4-erianin)](ClO4)2 (L1 = 2-(2-(tri-fluoromethyphenyl))-imidazo [4,5f][1-10]phenanthroline (1) and [Ru(phen)2(L2-(CH2)4-eria)](ClO4)2 (L2 = 2-(4-(tri-fluoromethyphenyl))-imidazo [4,5f][1,10]phenanthroline (2), have been synthesized and investigated as a potential G-quadruplex(G4) DNA stabilizer. Both complexes, especially 2, can bind to c-myc G4 DNA with high affinity by electronic spectra, and the binding constant calculated for 1 and 2 is about 15.1 and 2.05 × 107 M-1, respectively. This was further confirmed by the increase in fluorescence intensity for both complexes. Moreover, the positive band at 265 nm in the CD spectra of c-myc G4 DNA decreased treated with 2, indicating that 2 may bind to c-myc G4 DNA through extern groove binding mode. Furthermore, fluorescence resonance energy transfer (FRET) assay indicated that the melting point of c-myc G4 DNA treated with 1 and 2 increased 15.5 and 16.5 °C, respectively. Finally, molecular docking showed that 1 can bind to c-myc G4 DNA in the extern groove formed by base pairs G7-G9 and G22-A24, and 2 inserts into the small groove of c-myc G4 DNA formed by base pairs T19-A24. In summary, these ruthenium(II) complexes, especially 2, can be developed as potential c-myc G4 DNA stabilizers and will be exploited as potential anticancer agents in the future.
Assuntos
Complexos de Coordenação , Quadruplex G , Rutênio , Rutênio/química , Simulação de Acoplamento Molecular , Fenantrolinas/química , DNA/química , Complexos de Coordenação/químicaRESUMO
The interactions of ruthenium(II) complex with Glucose inhibited division protein A (GidA protein) was studied through various spectroscopic techniques with the ultimate goal of preparing adducts with good selectivity for cancer cells. In all the cases, formation of a tight metal-protein conjugate was observed. The influence of pH, reducing agents and chelators on the formation of adduct was analysed by UV- visible spectroscopy. While there was no effect on the addition of sodium ascorbate, some alterations on some selected bands were seen on the UV-visible spectra on the addition of EDTA. The adduct was stable in the pH range of 5-8. Addition of ruthenium(II) complex effectively quenched the intrinsic fluorescence of GidA and it occurred through static quenching. The effect of ruthenium(II) complex on the conformation of GidA has been examined by analyzing CD spectrum. Though, there was some conformational changes observed in the presence of ruthenium(II) complex, α- helix in the secondary structure of GidA retained its identity. Molecular docking of ruthenium(II) complex with GidA also indicated that GidA docks through hydrophobic interaction. The stable semisynthetic complex (ruthenium(II) complex with GidA) was checked for topoisomerase II inhibition. Relaxation and decatenation assay proved topoisomerase II inhibition of semisynthetic complex.Communicated by Ramaswamy H. Sarma.
Assuntos
Neoplasias , Rutênio , Humanos , Inibidores da Topoisomerase II/farmacologia , Simulação de Acoplamento Molecular , Proteína Estafilocócica A , Rutênio/farmacologia , Rutênio/química , Neoplasias/tratamento farmacológico , DNA Topoisomerases Tipo II/metabolismoRESUMO
In this article, ligand IPP (IPP = 4-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-N,N-diphenylaniline) and its three Ru(II) complexes: [Ru(bpy)2(IPP)](ClO4)2 (1) (bpy = 2,2'-bipyridine), [Ru(dmbpy)2(IPP)](ClO4)2 (2) (dmbpy = 4,4'-dimethyl-2,2'-bipyridine), and [Ru(phen)2(IPP)](ClO4)2 (3) (phen = 1,10-phenanthroline) were synthesized and characterized. The anticancer activity in vitro of the complexes was investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. The scratching and colony-forming experiments confirmed the complexes 1, 2, 3 interfered with the proliferation and migration ability of cells. The accumulation of the complexes in cells was researched and we found that these complexes directly accumulated in mitochondria, then the complexes cause a decline of the mitochondrial membrane potential and induce an increase of intracellular reactive oxygen species (ROS) levels. The growth of B16 cells were inhibited by 1, 2 and 3 at G0/G1 phase. Apoptosis was induced through mitochondrial pathway and the expression of apoptosis-related factors was regulated. In addition, the complexes promoted the transition of poly(ADP-ribose)polymerase (PARP) into the cleaved form (Cleaved PARP), downregulated the anti-apoptotic proteins, and upregulated the pro-apoptotic proteins. Consequently, complexes 1, 2 and 3 exerted their anticancer activity by regulating B-cell lymphoma-2 (Bcl-2) family proteins. Complex 2 showed excellent antitumor effects with a high inhibitory rate of 65.95% in vivo. Taken together, the complexes cause apoptosis in B16 cells through a ROS-mediated mitochondrial dysfunction pathway.
Assuntos
Antineoplásicos , Complexos de Coordenação , Rutênio , 2,2'-Dipiridil/farmacologia , Adenosina Difosfato Ribose/farmacologia , Antineoplásicos/farmacologia , Apoptose , Proteínas Reguladoras de Apoptose , Linhagem Celular Tumoral , Complexos de Coordenação/farmacologia , Ligantes , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Rutênio/farmacologiaRESUMO
So far, the polyphenolic components of turmeric have shown a significant pharmacological preventative activity for a wide spectrum of diseases, including oncological disorders. This type of natural product could be of great interest for the inhibition of cancer cell proliferation, displaying less side effects in comparison to classical chemotherapeutics. The poor bioavailability and quick metabolism of such natural compounds require new investigative methods to improve their stability in the organisms. A synthetic approach to increase the efficiency of curcuminoids is to coordinate them to metals through the beta-dicarbonyl moiety. We report the synthesis and the biological attempts on human ovarian carcinoma A2780 of ruthenium(II) complexes 1-4, containing curcuminoid ligands. The cytotoxicity of complexes 1-4 proves their antiproliferative capability, and a correlation between the IC50 values and NF-κB transcription factor, FGF-2, and MMP-9 levels was figured out through the principal component analysis (PCA).
Assuntos
Antineoplásicos , Curcumina , Neoplasias Ovarianas , Rutênio , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Curcumina/uso terapêutico , Diarileptanoides , Feminino , Fator 2 de Crescimento de Fibroblastos , Humanos , Ligantes , Metaloproteinase 9 da Matriz , Neoplasias Ovarianas/tratamento farmacológico , Rutênio/farmacologiaRESUMO
The use of polypyridyl Ru complexes to inhibit metastasis is a novel approach, and recent studies have shown promising results. We have reported recently that Ru (II) complexes gathering two 4,7-diphenyl-1,10-phenanthroline (dip) ligands and the one being 2,2'-bipyridine (bpy) or its derivative with a 4-[3-(2-nitro-1H-imidazol-1-yl)propyl (bpy-NitroIm) or 5-(4-{4'-methyl-[2,2'-bipyridine]-4-yl}but-1-yn-1-yl)pyridine-2-carbaldehyde semicarbazone (bpy-SC) moieties can alter the metastatic cascade, among others, by modulating cell adhesion properties. In this work, we show further studies of this group of complexes by evaluating their effect on HMEC-1 endothelial cells. While all the tested complexes significantly inhibited the endothelial cell migration, Ru-bpy additionally interrupted the pseudovessels formation. Functional changes in endothelial cells might arise from the impact of the studied compounds on cell elasticity and expression of proteins (vinculin and paxillin) involved in focal adhesions. Furthermore, molecular studies showed that complexes modulate the expression of cell adhesion molecules, which has been suggested to be one of the factors that mediate the activation of angiogenesis. Based on the performed studies, we can conclude that the investigated polypyridyl Ru (II) complexes can deregulate the functionality of endothelial cells which may lead to the inhibition of angiogenesis.
Assuntos
Complexos de Coordenação , Neoplasias , Rutênio , 2,2'-Dipiridil , Complexos de Coordenação/farmacologia , Células Endoteliais , Humanos , Ligantes , Fenantrolinas , Rutênio/farmacologiaRESUMO
The development of heteronuclear metal complexes as potent anticancer agents has received increasing attention in recent years. In this study, two new heteronuclear Ru(â ¡)-Re(â ) metal complexes, [Ru(bpy)2LRe(CO)3(DIP)](PF6)3 and [Ru(phen)2LRe(CO)3(DIP)](PF6)3 [RuRe-1 and RuRe-2, L = 2-(4-pyridinyl)imidazolio[4,5-f][1,10]phenanthroline, bpy = 2,2'-bipyridine, DIP = 4,7-diphenyl-1,10-phenanthroline, phen = 1,10-phenanthroline], were synthesized and characterized. Cytotoxicity assay shows that RuRe-1 and RuRe-2 exhibit higher anticancer activity than cisplatin, and exist certain selectivity toward human cancer cells over normal cells. The anticancer mechanistic studies reveal that RuRe-1 and RuRe-2 can induce apoptosis through the regulation of cell cycle, depolarization of mitochondrial membrane potential (MMP), elevation of intracellular reactive oxygen species (ROS), and caspase cascade. Moreover, RuRe-1 and RuRe-2 can effectively inhibit cell migration and colony formation. Taken together, heteronuclear Ru(â ¡)-Re(â ) metal complexes possess the prospect of developing new anticancer agents with high efficacy.
RESUMO
Two Ru(II) complexes, [Ru(phen)2(11-F-dppz)]2+ (Ru1, phen = 1,10-phenanthroline, 11-F-dppz = 11-fluorodipyrido[3,2-a:2',3'-c]phenazine) and [Ru(phen)2(11-CN-dppz)]2+ (Ru2, 11-CN-dppz = 11-cyanodipyrido[3,2-a:2',3'-c]phenazine), have been synthesized and characterized in this work. The binding properties of Ru1 and Ru2 with poly(A)â¢poly(U) RNA duplex have been investigated by spectroscopic methods and viscosity measurements. UV-vis absorption spectra and viscosity experiments demonstrate that the binding modes of Ru1 and Ru2 with poly(A)â¢poly(U) RNA duplex are intercalation, while the binding affinity for Ru2 is greater than that for Ru1. In addition, thermal denaturation studies reveal that both complexes significantly improve the stability of poly(A)â¢poly(U) duplex RNA. However, fluorescence titrations indicate that Ru1, unlike Ru2, can act as a molecular "light switch" for the poly(A)â¢poly(U) duplex RNA. The obtained results of this work indicate that the electron-withdrawing effect of substituents on the main ligands can significantly affect the binding of Ru(II) polypyridyl complexes with poly(A)â¢poly(U).
Assuntos
Complexos de Coordenação , Rutênio , Complexos de Coordenação/química , Fenazinas , Poli A/química , RNA/química , Rutênio/químicaRESUMO
Due to their optical and electrochemical properties, ruthenium(II) polypyridyl complexes have been used in a wide array of applications. Since the discovery of the light-switch ON effect of [Ru(bpy)2dppz]2+ when interacting with DNA, the design of new Ru(II) complexes as light-up probes for specific regions of DNA has been intensively explored. Amongst them, G-quadruplexes (G4s) are of particular interest. These structures formed by guanine-rich parts of DNA and RNA may be associated with a wide range of biological events. However, locating them and understanding their implications in biological pathways has proven challenging. Elegant approaches to tackle this challenge relies on the use of photoprobes capable of marking, reversibly or irreversibly, these G4s. Indeed, Ru(II) complexes containing ancillary π-deficient TAP ligands can create a covalently linked adduct with G4s after a photoinduced electron transfer from a guanine residue to the excited complex. Through careful design of the ligands, high selectivity of interaction with G4 structures can be achieved. This allows the creation of specific Ru(II) light-up probes and photoreactive agents for G4 labelling, which is at the core of this review composed of an introduction dedicated to a brief description of G-quadruplex structures and two main sections. The first one will provide a general picture of ligands and metal complexes interacting with G4s. The second one will focus on an exhaustive and comprehensive overview of the interactions and (photo)reactions of Ru(II) complexes with G4s.