Cytotoxic iron chelators: Characterization of the structure, solution chemistry and redox activity of ligands and iron complexes of the di-2-pyridyl ketone isonicotinoyl hydrazone (HPKIH) analogues

Di-2-pyridyl ketone isonicotinoyl hydrazone (HPKIH) and a range of its analogues comprise a series of monobasic acids that are capable of binding iron (Fe) as tridentate (N,N,O) ligands. Recently, we have shown that these chelators are highly cytotoxic, but show selective activity against cancer cells. Particularly interesting was the fact that cytotoxicity of the HPKIH analogues is maintained even after complexation with Fe. To understand the potent anti-tumor activity of these compounds, we have fully characterized their chemical properties. This included examination of the solution chemistry and X-ray crystal structures of both the ligands and Fe complexes from this class and the ability of these complexes to mediate redox reactions. Potentiometric titrations demonstrated that all chelators are present predominantly in their charge-neutral form at physiological pH (7.4), allowing access across biological membranes. Keto-enol tautomerism of the ligands was identified, with the tautomers exhibiting distinctly different protonation constants. Interestingly, the chelators form low-spin (diamagnetic) divalent Fe complexes in solution. The chelators form distorted octahedral complexes with Fe-II, with two tridentate ligands arranged in a meridional fashion. Electrochemistry of the Fe complexes in both aqueous and non-aqueous solutions revealed that the complexes are oxidized to their ferric form at relatively high potentials, but this oxidation is coupled to a rapid reaction with water to form a hydrated (carbinolamine) derivative, leading to irreversible electrochemistry. The Fe complexes of the HPKIH analogues caused marked DNA degradation in the presence of hydrogen peroxide. This observation confirms that Fe complexes from the HPKIH series mediate Fenton chemistry and do not repel DNA. Collectively, studies on the solution chemistry and structure of these HPKIH analogues indicate that they can bind cellular Fe and enhance its redox activity, resulting in oxidative damage to vital biomolecules.

Synthesis, characterization and redox behaviour of benzoyldiazenido- and oxorhenium complexes bearing N,N- and S,S-type ligands

The reactions of [ReCl2{eta(2)-N2C(O)Ph}(PPh3)(2)](1) with 2-aminopyrimidine (H(2)Npyrm), 2,2'-bipyridine (bpy) and tetraethylthiuram disulfide (tds), in MeOH upon reflux, lead to the new eta(1)-(benzoyldiazenido)-rhenium(III) complexes [ReCl{eta(1)-N2C(O)Ph}(HNpyrm)(PPh3)(2)](2)and [ReCl2{eta(1)-N2C(O)Ph}(bpy)(PPh3)] (3), and the known oxo(diethyldithiocarbamato)dirhenium(v)complex [Re2O2(mu O){Et2NC(S)S}(4)](4), respectively. The Et2NC(S)S ligands in 4 result from S-S bond rupture of tds molecules. The obtained compounds have been characterized by IR, H-1, P-31{H-1} and C-13{H-1} NMR spectroscopies, FAB(+)-MS, elemental and single-crystal X-ray diffraction (for 2 and 4)analyses. Complex 2 represents the first structurally characterized Re compound derived from 2-aminopyrimidine. Besides, the redox behaviour of 2-4 in CH2Cl2 solution has been studied by cyclic voltammetry, and the Lever electrochemical ligand parameter (E-L)has been estimated, for the first time, for HNpyrm. The electrochemical results are discussed in terms of electronic properties of the Re centres and the ligands.

Difusão molecular em ressonância magnética para estudo de lesões mamárias malignas

Objetivos – Com este estudo pretendeu-se i) avaliar o contributo da aplicação da sequência de difusão na caracterização das lesões mamárias malignas; ii) considerar se a sequência de difusão deve incorporar o protocolo standard em RM mamária e iii) correlacionar os resultados dos valores de coeficiente aparente de difusão (ADC) e os resultados histológicos. Metodologia – A amostra incluiu 18 pacientes do sexo feminino, com idades compreendidas entre 38 e 71 anos, que apresentavam lesões mamárias malignas confirmadas histologicamente. Foi adicionado ao protocolo de RM mamária a sequência de difusão, de modo a calcular os valores de ADC das lesões observadas. Resultados – Verificou-se que a range de valores de ADC para lesões malignas em ROI’s calculados no centro da lesão apresentavam uma média e desvio-padrão de (0,89 ± 0,14x10-3mm2/s). O método da utilização dos valores de ADC na caracterização de lesões mamárias malignas demonstrou uma sensibilidade de 100%. Conclusões – Neste estudo, com uma sensibilidade de 100%, a ponderação em difusão demonstrou ser uma técnica vantajosa na caracterização de lesões mamárias malignas pelo que se sugere a sua introdução no protocolo standard da RM mamária. ABSTRACT - Aims – The aim of this study was i) to evaluate the potential of the DWI sequence in the characterization of malignant breast lesions; ii) to verify if this sequence should incorporate the breast MRI protocol and iii) to correlate the apparent diffusion coefficients (ADC) values and histological results. Methodology – The sample includes 18 female patients between the ages of 38 and 71 years, who presented with malignant breast lesion confirmed by histology. The DWI sequence was added to the MRI standard protocol to calculate the ADC values. Results – In the results obtained we observed that the range of the ADC values calculated in the center of the malignant lesions, showed a mean and standard deviation of 0.89 ± 0.14 x10-3 mm2 / s. This method of using the ADC values for the detection of malignant lesions showed a sensitivity of 100%. Conclusion – The DWI technique proved to be a useful method in the characterization of malignant breast lesions, as it showed a sensitivity of 100%, so we suggest its inclusion in the Breast MR standard protocol.

Biochemical and structural characterization of β-lactamases tem-180 and tem-201

With the constant development of new antibiotics, selective pressure is a force to reckon when investigating antibiotic resistance. Although advantageous for medical treatments, it leads to increasing resistance. It is essential to use more potent and toxic antibiotics. Enzymes capable of hydrolyzing antibiotics are among the most common ways of resistance and TEM variants have been detected in several resistant isolates. Due to the rapid evolution of these variants, complex phenotypes have emerged and the need to understand their biological activity becomes crucial. To investigate the biochemical properties of TEM-180 and TEM-201 several computational methodologies have been used, allowing the comprehension of their structure and catalytic activity, which translates into their biological phenotype. In this work we intent to characterize the interface between these proteins and the several antibiotics used as ligands. We performed explicit solvent molecular dynamics (MD) simulations of these complexes and studied a variety of structural and energetic features. The interfacial residues show a distinct behavior when in complex with different antibiotics. Nevertheless, it was possible to identify some common Hot Spots among several complexes – Lys73, Tyr105 and Glu166. The structural changes that occur during the Molecular Dynamic (MD) simulation lead to the conclusion that these variants have an inherent capacity of adapting to the various antibiotics. This capability might be the reason why they can hydrolyze antibiotics that have not been described until now to be degraded by TEM variants. The results obtained with computational and experimental methodologies for the complex with Imipenem have shown that in order to this type of enzymes be able to acylate the antibiotics, they need to be capable to protect the ligand from water molecules.

Incorporation of niobium in SAPO-11 materials: Synthesis and characterization

The present work concerns a new synthesis approach to prepare niobium based SAPO materials with AEL structure and the characterization ofNb species incorporated within the inorganic matrixes. The SAPO-11 materials were synthesized with or without the help of a small amine, methylamine (MA) as co-template, while Nb was added directly during the preparation of the initial gel. Structural, textural and acidic properties of the different supports were evaluated by XRD, TPR, UV-Vis spectroscopy, pyridine adsorption followed by IR spectroscopy and thermal analyses. Pure and well crystalline Nb based SAPO-11 materials were obtained, either with or without MA, using in the initial gel a low Si content of about 0.6. Increasing the Si content of the gel up to 0.9 led to an important decrease of the samples crystallinity. Niobium was found to incorporate the AEL pores support as small Nb2O5 oxide particles and also as extra framework cationic species (Nb5+), compensating the negative charges from the matrix and generating new Lewis acid sites. (C) 2011 Elsevier Inc. All rights reserved.