Assessing the role of membrane lipids in the action of ruthenium(III) anticancer compounds.

This work addresses the possible role of the cell membrane in the molecular mechanism of action of two salan-type ruthenium complexes that were previously shown to be active against human tumor cells, namely [Ru(III)(L1)(PPh3)Cl] and [Ru(III)(L2)(PPh3)Cl] (where L1 is 6,6'-(1R,2R)-cyclohexane-1,2-diylbis(azanediyl)bis(methylene)bis(3-methoxyphenol); and L2 is 2,2'-(1R,2R)-cyclohexane-1,2-diylbis(azanediyl)bis(methylene)bis(4-methoxyphenol)). One-component membrane models were first used, a disordered fluid bilayer of dioleoylphosphatodylcholine (DOPC), and an ordered rigid gel bilayer of dipalmitoylphosphatidylcholine. In addition, two quaternary mixtures of phosphatidylcholine, phosphatidylethanolamine, sphingomyelin and cholesterol were used to mimic the lipid composition either of mammalian plasma membrane (1:1:1:1 mol ratio) or of a cancer cell line membrane (36.2:23.6:6.8:33.4 mol ratio). The results show that both salan ligands L1 and L2 bind relatively strongly to DOPC bilayers, but without significantly affecting their structure. The ruthenium complexes have moderate affinity for DOPC. However, their impact on the membranes was notable, leading to a significant increase in the permeability of the lipid vesicles. None of the compounds compromised liposome integrity, as revealed by dynamic light scattering. Fluorescence spectroscopy studies revealed changes in the biophysical properties of all membrane models analyzed in the presence of the two complexes, which promoted an increased fluidity and water penetration into the lipid bilayer in the one-component systems. In the quaternary mixtures, one of the complexes had an analogous effect (increasing water penetration), whereas the other complex reorganized the liquid ordered and liquid disordered domains. Thus, small structural differences in the metal ligands may lead to different outcomes. To better understand the effect of these complexes in cancer cells, the membrane dipole potential was also measured. For both Ru complexes, an increase in the dipole potential was observed for the cancer cell membrane model, while no alteration was detected on the non-cancer plasma membrane model. Our results show that the action of the Ru(III) complexes tested involves changes in the biophysical properties of the plasma membrane, and that it also depends on membrane lipid composition, which is frequently altered in cancer cells when compared to their normal counterparts.

Homens envenenados como sujeitos do cuidar e dos cuidados de enfermagem / Poisoned men as subjects of care and nursing care

Caracterizar e analisar os envenenamentos por carbamato ("chumbinho") em homens. Métodos: Estudo de casos múltiplos através de observação não-participante, realizado em cinco homens atendidos em um serviço de emergência. Dados analisados através de análise temática, utilizando-se o software Atlas.ti versão 6.2. Resultados: A faixa etária variou entre 28 e 52 anos. Predominou a autoingestão, todos os estavam desempregados. Três eram solteiros. Todos apresentavam-se sujos, evacuados, urinados, com saliva, vômito e resíduos alimentares pelo corpo. Necessitavam de cuidados de higiene oral e corporal, troca das roupas sujas por outras limpas e secas e de aquecimento corporal. Conclusão: Este estudo corrobora os princípios da PNAISH ao identificar que a população masculina somente acessa o sistema de saúde por meio da atenção especializada. Todos os casos a via de intoxicação foi a via oral. Evidenciou-se como limitações a impossibilidade de abranger a totalidade das intoxicações e o fato das vítimas serem de demanda espontânea na emergência...

Alkyl deoxy-arabino-hexopyranosides: synthesis, surface properties, and biological activities.

Octyl and dodecyl glycosides possessing 2-deoxy-arabino-hexopyranoside moieties belonging to the D- and L-series in their alpha- and beta-forms were synthesized by reaction of an acetyl protected glycal with octanol or dodecanol, catalyzed by triphenylphosphine hydrobromide, followed by deprotection. Their surface properties were studied and discussed in terms of the adsorption and aggregation parameters, pC(20), CMC, and gamma(CMC). The antimicrobial activities were assessed using the paper disk diffusion and broth dilution methods. Both the octyl and dodecyl 2-deoxy beta-D-glycosides inhibited significantly Enterococcus faecalis, a microbe also highly susceptible to dodecyl 2,6-dideoxy-alpha-L-arabino-hexopyranoside. This compound was particularly active against Bacillus cereus and Bacillus subtilis, presenting for both Bacillus species a minimal inhibitory concentration of the same order of magnitude and a minimal lethal concentration even smaller than that obtained for chloramphenicol, a bioactivity which remained unaltered after 1 year solution storage at 4 degrees C. In addition, activity over Listeria monocytogenes was also observed. Direct cytotoxicity and genotoxicity of the glycosides were determined by proliferative index (mitotic index) evaluation in peripheral human lymphocytes of healthy donors. All compounds induced acute toxicity effects, and the response was dose dependent for the alpha-anomer of both the alkyl 2-deoxy-arabino-hexopyranosides and for the corresponding dodecyl beta-anomer, what suggests that non-toxic but still bioactive concentrations may be found for these compounds.

Synthesis, surface active and antimicrobial properties of new alkyl 2,6-dideoxy-L-arabino-hexopyranosides.

Synthesis of alkyl 2,6-dideoxy-L-arabino-hexopyranosides was accomplished by the reaction of 1,5-anhydro-2,6-dideoxy-L-arabino-hex-1-enitol with fatty alcohols in dichloromethane, catalyzed by triphenylphosphine hydrobromide. Reaction with octanol and dodecanol gave the corresponding alpha-glycosides in 50% and 42% yield, the beta-glycosides in 20% and 21% yield and the alpha-anomer of the Ferrier product in 10% and 9% yield, respectively. Deacetylation of the alpha-/beta-glycosides with sodium methoxide in methanol afforded the amphiphilic L-arabino-hexopyranosides in 94-99% yield. The surface tension at the air-water interface of the octyl L-glycosides and of the dodecyl alpha-L-glycoside aqueous solutions at 35 degrees C was measured with a du Noüy ring tensiometer and surface properties such as critical micelle concentration (CMC), relative surface excess, molecular area at the interface and Gibbs micellization free energy were evaluated. The stereochemistry of the hexopyranoside ring in unimers and aggregates is correlated to the hydrophobicity and packing efficiency on the air-water interface. The antibacterial and antifungal activities of the surface-active glycosides were evaluated using the paper disk diffusion method. The dodecyl alpha-L-arabino-hexopyranoside was quite active over Bacillus cereus and Bacillus subtilis, while low activity was found for this glycoside over Enterococcus faecalis and Listeria monocytogenes. The octyl glycosides tested showed low activity over almost all the above-mentioned bacteria, and also over the fungus Candida albicans. No inhibition of Salmonella enteritidis and of the filamentous fungus Aspergillus niger was detected for any of the compounds tested.