RESUMO
Antimicrobial resistance has become a global threat to human health, which is coupled with the lack of novel drugs. Metallocompounds have emerged as promising diverse scaffolds for the development of new antibiotics. Herein, we prepared some metal compounds mainly focusing on cis-[Ru(bpy)(dppz)(SO3)(NO)](PF6) (PR02, bpy = 2,2'-bipyridine, dppz = dipyrido[3,2-a:2',3'-c]phenazine), in which phenazinic and nitric oxide ligands along with sulfite conferred some key properties. This compound exhibited a redox potential for bound NO+/0 of -0.252 V (vs. Ag|AgCl) and a high pH for nitrosyl-nitro conversion of 9.16, making the nitrosyl ligand the major species. These compounds were still able to bind to DNA structures. Interestingly, reduced glutathione (GSH) was unable to promote significant NO/HNO release, an uncommon feature of many similar systems. However, this reducing agent was essential to generate superoxide radicals. Antimicrobial studies were carried out using six bacterial strains, where none or very low activity was observed for Gram-negative bacteria. However, PR02 and PR (cis-[Ru(bpy)(dppz)Cl2]) showed high antibacterial activity in some Gram-positive strains (MBC for S. aureus up to 4.9 µmol L-1), where the activity of PR02 was similar to or at least 4-fold better than that of PR. Besides, PR02 showed capacity to inhibit bacterial biofilm formation, a major health issue leading to bacterial tolerance to antibiotics. Interestingly, we also showed that PR02 can function in synergism with the known antibiotic ampicillin, improving their action up to 4-fold even against resistant strains. Altogether, these results showed that PR02 is a promising antimicrobial nitrosyl ruthenium compound combining features beyond its killing action, which deserves further biological studies.
Assuntos
Antibacterianos , Biofilmes , Complexos de Coordenação , Testes de Sensibilidade Microbiana , Fenazinas , Rutênio , Fenazinas/química , Fenazinas/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Rutênio/química , Rutênio/farmacologia , Biofilmes/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química , Sinergismo Farmacológico , Staphylococcus aureus/efeitos dos fármacosRESUMO
Osteosarcoma cancers are becoming more common in children and young adults, and existing treatments have low efficacy and a very high mortality rate, making it pressing to search for new chemotherapies with high efficacy and high selectivity index. Copper complexes have shown promise in the treatment of osteosarcoma. Here, we report the synthesis, characterization, and anticancer activity of [Cu(N-N-Fur)(NO3)(H2O)] complex where N-N-Fur is (E)-N'-(2-hydroxy-3-methoxybenzylidene)furan-2-carbohydrazide. The [Cu(N-N-Fur)(NO3)(H2O)] complex was characterized via X-ray diffraction and electron spin resonance (ESR), displaying a copper center in a nearly squared pyramid environment with the nitrate ligand acting as a fifth ligand in the coordination sphere. We observed that [Cu(N-N-Fur)(NO3)(H2O)] binds to DNA in an intercalative manner. Anticancer activity on the MG-63 cell line was evaluated in osteosarcoma monolayer (IC50 2D: 1.1 ± 0.1 µM) and spheroids (IC50 3D: 16.3 ± 3.1 µM). Selectivity assays using nontumoral fibroblast (L929 cell line) showed that [Cu(N-N-Fur)(NO3)(H2O)] has selectivity index value of 2.3 compared to cis-diamminedichloroplatinum(II) (CDDP) (SI = 0.3). Additionally, flow cytometry studies demonstrated that [Cu(N-N-Fur)(NO3)(H2O)] inhibits cell proliferation and conveys cells to apoptosis. Cell viability studies of MG-63 spheroids (IC50 = 16.3 ± 3.1 µM) showed that its IC50 value is 4 times lower than for CDDP (IC50 = 65 ± 6 µM). Besides, we found that cell death events mainly occurred in the center region of the spheroids, indicating efficient transport to the microtumor. Lastly, the complex showed dose-dependent reductions in spheroid cell migration from 7.5 to 20 µM, indicating both anticancer and antimetastatic effects.
Assuntos
Neoplasias Ósseas , Osteossarcoma , Criança , Humanos , Adulto Jovem , Cobre/farmacologia , Ligantes , Osteossarcoma/tratamento farmacológicoRESUMO
The role of metal complexes on facing DNA has been a topic of major interest. However, metallonitrosyl compounds have been poorly investigated regarding their reactivities and interaction with DNA. A nitrosyl compound, cis-[Ru(bpy)2(SO3)(NO)](PF6)(A), showed a variety of promising biological activities catching our attention. Here, we carried out a series of studies involving the interaction and damage of DNA mediated by the metal complex A and its final product after NO release, cis-[Ru(bpy)2(SO3)(H2O](B). The fate of DNA with these metal complexes was investigated upon light or chemical stimuli using electrophoresis, electronic absorption spectroscopy, circular dichroism, size-exclusion resin, mass spectrometry, electron spin resonance (ESR) and viscometry. Since many biological disorders involve the production of oxidizing species, it is important to evaluate the reactivity of these compounds under such conditions as well. Indeed, the metal complex B exhibited important reactivity with H2O2 enabling DNA degradation, with detection of an unusual oxygenated intermediate. ESR spectroscopy detected mainly the DMPO-OOH adduct, which only emerges if H2O2 and O2 are present together. This result indicated HOO⢠as a key radical likely involved in DNA damage as supported by agarose gel electrophoresis. Notably, the nitrosyl ruthenium complex did not show evidence of direct DNA damage. However, its aqua product should be carefully considered as potentially harmful to DNA deserving further in vivo studies to better address any genotoxicity.
Assuntos
Complexos de Coordenação , Rutênio , Rutênio/química , Complexos de Coordenação/química , Peróxido de Hidrogênio , Compostos de Rutênio/química , Óxido Nítrico/química , DNARESUMO
Improving the binding of metal complexes to DNA to boost cancer cell cytotoxicity requires fine tuning of their structural and chemical properties. Copper has been used as a metal center in compounds containing intercalating ligands due to its ability to catalytically generate reactive oxygen species (ROS), such as hydroxyl radicals (OHË). We envision the synergy of DNA binding and ROS generation in proximity to target DNA as a powerful chemotherapy treatment. Here, we explore the use of [Cu(2CP-Bz-SMe)]2+ (2CP-Bz-SMe = 1,3-bis(1,10-phenanthrolin-2-yloxy)-N-(4-(methylthio)benzylidene)propan-2-amine) for this purpose by characterizing its cytotoxicity, DNA binding, and ability to affect DNA replication through the polymerase chain reaction - PCR and nuclease assays. We determined the binding (Kb) and Stern-Volmer constants (KSV) for complex-DNA association of 5.8 ± 0.14 × 104 and 1.64 (±0.08), respectively, through absorption titration and competitive fluorescence experiments. These values were superior to those of other Cu-complex intercalators. We hypothesize that the distorted trigonal bipyramidal geometry of [Cu(2CP-Bz-SMe)]2+ allows the phenanthroline fragments to be better accommodated into the DNA double helix. Moreover, the aromaticity of these fragments increases the local hydrophobicity thus increasing the affinity for the hydrophobic domains of DNA. Nuclease assays in the presence of common reducing agents ascorbic acid, nicotinamide adenine dinucleotide, and glutathione showed the effective degradation of DNA due to the in situ generation of OHË. The [Cu(2CP-Bz-SMe)]2+ complex showed cytotoxicity against the following human cancer cells lines A549, MCF-7, MDA-MB-231 and MG-63 with half maximal inhibitory concentration (IC50) values of 4.62 ± 0.48, 5.20 ± 0.76, 5.70 ± 0.42 and 2.88 ± 0.66 µM, respectively. These low values of IC50, which are promising if compared to that of cisplatin, are ascribed to the synergistic effect of ROS generation with the intercalation ability into the DNA minor grooves and blocking DNA replication. This study introduces new principles for synergizing the chemical and structural properties of intercalation compounds for improved drug-DNA interactions targeting cancer.
Assuntos
Cobre , Complexos de Coordenação , FenantrolinasRESUMO
Se presenta el caso de un lactante de 18 meses de edad, del sexo masculino, de la raza blanca y eutrófico, al que se le diagnostica al mes de ingresado una hemosiderosis pulmonar primaria. Como hallazgo anatomopatológico encontramos, además de la hemosiderosis pulmonar, una hipertrofia cardíaca, riñones difíciles de descapsular con superficie granular, un estudio hístico compatible con una glomerulonefritis crónica. En la radiografía torácica se observaron infiltrados difusos parabiliares. El diagnóstico se basó fundamentalmente en la presencia de macrófagos cargados de hemosiderina en secreciones bronquiales. El paciente falleció a los 4 meses de efectuado el diagnóstico