Iron and copper complexes with antioxidant activity as inhibitors of the metastatic potential of glioma cells.

Gliomas are the most common type of primary brain tumors, presenting high mortality and recurrence rates that highlight the need for the development of more efficient therapies. In that context, we investigated iron(iii) (FeL) and copper(ii) (CuL) complexes containing the tetradentate ligand 2-{[(3-chloro-2-hydroxy-propyl)-pyridin-2-ylmethyl-amino]-methyl}-phenol (L) as potential antimetastatic compounds in glioma cells. These complexes were designed to act as mimetics of antioxidant metalloenzymes (catalases and superoxide dismutase) and thus interfere with the production of reactive oxygen species (ROS), important signaling molecules that have been linked to the induction of Epithelial-Mesenchymal Transition (EMT) in cancer cells, a process associated with cancer invasion and aggressiveness. The results obtained have revealed that, in vitro, both compounds act as superoxide dismutase or catalase mimetics, and this translated in glioma cells into a decrease in ROS levels in FeL-treated cells. In addition, both complexes were found to inhibit the migration of monolayer-grown H4 cells and lead to decreased expression of EMT markers. More importantly, this behavior was recapitulated in 3D spheroids models, where CuL in particular was found to completely inhibit the invasion ability of glioma cells, with or without cellular irradiation with X-rays, which is suggestive of these compounds' potential to be used in combination with radiotherapy. Overall, the results herein obtained describe the novel use of these complexes as agents that are able to interfere with regulation of EMT and the invasive behavior of glioma cells, an application that deserves to be further explored.

A New Mixed-Valence Mn(II)Mn(III) Compound With Catalase and Superoxide Dismutase Activities.

The synthesis, X-ray molecular structure, physico-chemical characterization and dual antioxidant activity (catalase and superoxide dismutase) of a new polymeric mixed valence Mn(III)Mn(II) complex, containing the ligand H2BPClNOL (N-(2-hydroxybenzyl)-N-(2-pyridylmethyl)[(3-chloro)(2-hydroxy)] propylamine) is described. The monomeric unit is composed of a dinuclear Mn(II)Mn(III) moiety, [Mn(III)(µ-HBPClNOL)(µ-BPClNOL)Mn(II)(Cl)](ClO4)·2H2O, 1, in which the Mn ions are connected by two different bridging groups provided by two molecules of the ligand H2BPClNOL, a phenoxide and an alkoxide group. In the solid state, this mixed valence dinuclear unit is connected to its neighbors through chloro bridges. Magnetic measurements indicated the presence of ferromagnetic [J = +0.076(13) cm-1] and antiferromagnetic [J = -5.224(13) cm-1] interactions. The compound promotes O 2 • - dismutation in aqueous solution (IC50 = 0.370 µmol dm-3, k cat = 3.6x106 M-1 s-1). EPR studies revealed that a high-valent Mn(III)-O-Mn(IV) species is involved in the superoxide dismutation catalytic cycle. Complex 1 shows catalase activity only in the presence of a base, e.g., piperazine or triethylamine. Kinetic studies were carried out in the presence of piperazine and employing two different methods, resulting in k cat values of 0.58 ± 0.03 s-1 (detection of O2 production employing a Clark electrode) and 2.59 ± 0.12 s-1 (H2O2 consuption recorded via UV-Vis). EPR and ESI-(+)-MS studies indicate that piperazine induces the oxidation of 1, resulting in the formation of the catalytically active Mn(III)-O-Mn(IV) species.

Avaliação da atividade antibacteriana e moduladora dos extratos metanólico e hexânico da folha de Allium cepa / Evaluation of the Antibacterial and Modulating Activity of Methanolic and Hexanic Extracts of the Allium Cepa / Evaluación de la actividad antibacteriana y moduladora de los extractos metanol y hexano de la hoja de Allium cepa

Introdução: A resistência bacteriana tem crescido significativamente nos últimos tempos, tornando-se imprescindível a busca por novos alvos terapêuticos. Nesse contexto, compostos bioativos presentes em algumas plantas medicinais podem apresentar várias atividades biológicas, como ação antimicrobiana. Allium cepa conhecida popularmente como cebola é utilizada de maneira etnofarmacológica há muito tempo para o tratamento de diversas enfermidades: tuberculose, diabetes, hipertensão, reumatismo e assim por diante. Objetivo: O principal objetivo deste trabalho foi avaliar a atividade antimicrobiana e modulatória dos extratos metanólico e hexânicoda das folhas A. cepa frente às cepas de bactérias padrões e multirresistentes. Materiais e métodos: Pelos métodos e microdiluição e modulação com antibióticos. Resultados: Os resultados deste estudo demonstraram uma variação no CMI (Concentração Inibitória Mínima) de 128 a ≥ 1024 μg/mL dos extratos metanólico de A. cepa (EMAC) e hexânico de A. cepa (EHAC). Na modulação com os aminoglicosídeos (amicacina e gentamicina) observaram-se efeitos sinérgicos e antagônicos dos extratos EHAC e EMAC frente às cepas Escherichia coli e Staphylococcus aureus de linhagem multirresistente. Novas pesquisas são necessárias para uma possível utilização das plantas medicinais combinadas com os antimicrobianos frente às linhagens patogênicas. Conclusão: Através desses resultados sugere-se que os produtos naturais representam fontes promissoras no combate à resistência bacteriana.

Introduction: Bacterial resistance has grown significantly in recent years, making the search for new antibiotics imperative. Bioactive compounds in some medicinal plants may exhibit various biological activities as antimicrobial activity. Allium cepa, popularly known as onion, is ethnopharmacologically used for treating various diseases, such as tuberculosis, diabetes, hypertension and rheumatism; it is also considered a powerful bactericide. Objective: The main objective of this study was to evaluate the antimicrobial and modulating activity of methanol and hexane extracts of A. cepa against the strains of multiresistant bacteria. Materials and methods: Microdilution and modulation of antibiotics. Results: The results showed a variation in the MIC (Minimum Inhibitory Concentration) from 128 to ≥ 1024μg / mL between A. cepa methanol (EMAC) and A. cepa hexane (EHAC) extracts. Modulation with aminoglycosides (gentamicin and amikacin) have proved to have antagonistic effects of the extracts sinérgicose EHAC and EMAC against strains of multiresistant Escherichia coli and Staphylococcus aureus. Further research is needed related to the use of medicinal plants combined with antimicrobials against pathogenic strains. Conclusion: Through these results it can be inferred that natural products could constitute a promising source for combating bacterial resistance.

Introducción: la resistencia bacteriana ha crecido significativamente en los últimos años, por lo que es necesaria la búsqueda de nuevas dianas terapéuticas. En este contexto, los compuestos bioactivos presentes en algunas plantas medicinales pueden tener diversas actividades biológicas, tales como la acción antimicrobiana. Allium cepa, conocida como la cebolla, es utilizada, popularmente de forma etnofarmacológica para el tratamiento de diversas enfermedades tales como la tuberculosis, la diabetes, la hipertensión, el reumatismo y así sucesivamente. Objetivo: el objetivo de este estudio fue evaluar la actividad antimicrobiana y moduladora de extractos de metanol y hexano de Allium cepa frente a las cepas de bacterias y normas multirresistentes. Materiales y métodos: por los métodos microdilución y modulación con antibióticos. Resultados: los resultados mostraron una variación de MIC(concentración mínima inhibitoria) de 128 a ≥ 1024μg / mL dos extractos metanólicos A. cepa (EMAC) y hexano de A. cepa (EHAC). En la modulación con aminoglucósidos (amikacina y gentamicina), se observaron efectos sinérgicos y antagónicos de EHAC y EMAC, frente a las cepas de Escherichia coli y Staphylococcus aureus multirresistente. Se necesitan nuevas investigaciones para un posible uso de plantas medicinales combinadas con la cara antimicrobiana de las cepas patógenas. Conclusión: a partir de estos resultados, se sugiere que los productos naturales son fuentes prometedoras en la lucha contra la resistencia bacteriana.

Iron, copper, and manganese complexes with in vitro superoxide dismutase and/or catalase activities that keep Saccharomyces cerevisiae cells alive under severe oxidative stress.

Due to their aerobic lifestyle, eukaryotic organisms have evolved different strategies to overcome oxidative stress. The recruitment of some specific metalloenzymes such as superoxide dismutases (SODs) and catalases (CATs) is of great importance for eliminating harmful reactive oxygen species (hydrogen peroxide and superoxide anion). Using the ligand HPClNOL {1-[bis(pyridin-2-ylmethyl)amino]-3-chloropropan-2-ol}, we have synthesized three coordination compounds containing iron(III), copper(II), and manganese(II) ions, which are also present in the active site of the above-noted metalloenzymes. These compounds were evaluated as SOD and CAT mimetics. The manganese and iron compounds showed both SOD and CAT activities, while copper showed only SOD activity. The copper and manganese in vitro SOD activities are very similar (IC50~0.4 µmol dm(-3)) and about 70-fold higher than those of iron. The manganese compound showed CAT activity higher than that of the iron species. Analyzing their capacity to protect Saccharomyces cerevisiae cells against oxidative stress (H2O2 and the O2(•-) radical), we observed that all compounds act as antioxidants, increasing the resistance of yeast cells mainly due to a reduction of lipid oxidation. Especially for the iron compound, the data indicate complete protection when wild-type cells were exposed to H2O2 or O2(•-) species. Interestingly, these compounds also compensate for both superoxide dismutase and catalase deficiencies; their antioxidant activity is metal ion dependent, in the order iron(III)>copper(II)>manganese(II). The protection mechanism employed by the complexes proved to be independent of the activation of transcription factors (such as Yap1, Hsf1, Msn2/Msn4) and protein synthesis. There is no direct relation between the in vitro and the in vivo antioxidant activities.