Two new ternary complexes of copper(II) with tetracycline or doxycycline and 1,10-phenanthroline and their potential as antitumoral: cytotoxicity and DNA cleavage

This paper reports on the synthesis and characterization of two new ternary copper(II) complexes: [Cu(doxycycline)(1,10-phenanthroline)(H(2)O)(ClO(4))](ClO(4)) (1) and [Cu(tetracycline)(1,10-phenanthroline)(H(2)O)(ClO(4))](ClO(4)) (2). These compounds exhibit a distorted tetragonal geometry around copper, which is coordinated to two bidentate ligands, 1,10-phenanthroline and tetracycline or doxycyline, a water molecule, and a perchlorate ion weakly bonded in the axial positions. In both compounds, copper(II) binds to tetracyclines via the oxygen of the hydroxyl group and oxygen of the amide group at ring A and to 1,10-phenanthroline via its two heterocyclic nitrogens. We have evaluated the binding of the new complexes to DNA, their capacity to cleave it, their cytotoxic activity, and uptake in tumoral cells. The complexes bind to DNA preferentially by the major groove, and then cleave its strands by an oxidative mechanism involving the generation of ROS. The cleavage of DNA was inhibited by radical inhibitors and/or trappers such as superoxide dismutase, DMSO, and the copper(I) chelator bathocuproine. The enzyme T4 DNA ligase was not able to relegate the products of DNA cleavage, which indicates that the cleavage does not occur via a hydrolytic mechanism. Both complexes present an expressive plasmid DNA cleavage activity generating single- and double-strand breaks, under mild reaction conditions, and even in the absence of any additional oxidant or reducing agent. In the same experimental conditions, [Cu(phen)(2)](2+) is approximately 100-fold less active than our complexes. These complexes are among the most potent DNA cleavage agents reported so far. Both complexes inhibit the growth of K562 cells with the IC(50) values of 1.93 and 2.59 μmol L(-1) for compounds 1 and 2, respectively. The complexes are more active than the free ligands, and their cytotoxic activity correlates with intracellular copper concentration and the number of Cu-DNA adducts formed inside cells.     

Photoinduced DNA cleavage promoted by two copper(II) complexes of tetracyclines and 1,10-phenanthroline

In this report, we demonstrate how UV-light exposure can enhance DNA cleavage promoted by two copper(II) complexes of tetracyclines and 1,10-phenanthroline about 40 times in comparison to nonirradiated conditions. In addition, new aspects regarding their DNA binding properties, as well as the mechanism of the cleavage reaction, were also investigated.     

Optimization of <Emphasis Type="Italic">α</Emphasis>-Terpineol Production by the Biotransformation of <Emphasis Type="Italic">R</Emphasis>-(+)-Limonene and (−)-β-Pinene

The main objective of this work is to present the optimization of the biotransformation of R-(+)-limonene and (−)-β-pinene aiming at the production of α-terpineol by strains of fungal and yeasts previously isolated by our research group using the methodology of experimental design. New optimized experimental data on α-terpineol production by the biotransformation of R-(+)-limonene and (−)-β-pinene using newly isolated microorganisms are reported in this work. Conversion of about 1,700 mg/L was achieved when R-(+)-limonene was used as substrate and the newly isolated strain 05.01.35 as microorganism at the central point of the experimental design, corresponding to a substrate concentration of 1.75%, mass of inoculum of 2 g, and substrate to ethanol volume ratio of 1:1. The same experimental condition led to higher conversions when (−)-β-pinene was used as substrates and the strains coded as 04.05.08 and 01.04.03 as microorganism. Here, conversions of about 770 mg/L were achieved.     

Assessment of the in vivo genotoxicity of new lead compounds to treat sickle cell disease

The compounds 1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl nitrate (C1), (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl nitrate (C2), 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)benzyl nitrate (C3), 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-hydroxy-benzenesulfonamide (C4), 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)benzyl nitrate (C5), and 2-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]ethyl nitrate (C6) were evaluated with a micronucleus test using mouse peripheral blood to identify new candidate drugs for the treatment of sickle cell disease (SCD) that are safer than hydroxyurea. The compounds induced an average frequency of micronucleated reticulocytes (MNRET) of less than six per 1,000 cells at 12.5, 25, 50, and 100 mg/kg, whereas hydroxyurea induced an average MNRET frequency of 7.8, 9.8, 15, and 33.7 per 1000 cells respectively, at the same concentrations. Compounds C1-C6 are new non-genotoxic in vivo candidate drugs for the treatment of SCD symptoms.     

Quantum gravity at the LHC

We study the production of massless gravitons at the LHC and compare our results to those obtained in extra-dimensional models. The signature in both cases is missing energy plus jets. In case of non-observation, the LHC could be used to put the tightest limit to date on the value of the Planck mass.     

Homogenization towards a mechanistic Rigid Body and Spring Model (HRBSM) for the non-linear dynamic analysis of 3D masonry structures

A mechanistic model with rigid elements and interfaces suitable for the non-linear dynamic analysis of full scale 3D masonry buildings is presented. The model relies into two steps: in the first step, a simplified homogenization is performed at the meso-scale to deduce the mechanical properties of a macroscopic material, to be used in structural applications; the second step relies into the implementation of a Rigid Body and Spring Model (RBSM) constituted by rigid elements linked with homogenized interfaces. In the homogenization step, a running bond elementary cell is discretized with 24 three-node plane-stress elastic triangular elements and non-linear interfaces representing mortar joints. It is shown how the mechanical problem in the unit cell is characterized by few displacement variables and how homogenized stress–strain curves can be evaluated by means of a semi-analytical approach. The second step relies on the implementation of the homogenized curves into a RBSM, where an entire masonry structure can be analyzed in the non-linear dynamic range through a discretization with rigid elements and inelastic interfaces. Non-linear structural analyses are conducted on a church façade interconnected with a portion of the perpendicular walls and on a small masonry building, for which experimental and numerical data are available in the literature, in order to show how quite reliable results may be obtained with a limited computational effort.     

A fast and general upper-bound limit analysis approach for out-of-plane loaded masonry walls

A new general approach for the limit analysis of out-of-plane loaded masonry walls based on an upper bound formulation is presented. A given masonry wall of generic form presenting openings of arbitrary shape is described through its Non-Uniform Rational B-Spline (NURBS) representation in the three-dimensional Euclidean space. A lattice of nodes is defined in the parameters space together with possible fracture lines. An initial set of rigid elements initially subdividing the original wall geometry is identified accordingly. A homogenized upper bound limit analysis formulation, which takes into account the main characteristics of masonry material such as very low resistance in traction and anisotropic behavior is deduced. Moreover the effect of vertical loads and membrane stresses is considered, assuming internal dissipation allowed exclusively along element edges. A number of technically meaningful examples prove that a good estimate of the collapse load multiplier is obtained, provided that the initial net of yield lines is suitably adjusted by means of a meta-heuristic approach (i.e. a Genetic Algorithm, GA) in order to enforce that element edges accurately represent the actual failure mechanism.     

Probing the chemical reactivity of free titanium clusters by x-ray absorption spectroscopy

Synchrotron radiation-based experimental techniques are largely employed for the characterization of the reactivity of finite size systems; in particular, x-ray absorption spectroscopy (XAS) is a suitable tool to shed light on the local electronic structure and chemical status of atoms in nano-objects, as it is very sensitive to the local bonding environment of the probed site. In supported clusters intrinsic properties and reactivity are largely distorted and obscured by the changes imposed by the growth procedure and by the influence of the substrate, so the attainability of experiments on free clusters reacting with species in the gas phase is a primary goal in the development of cluster science. In this paper we report a proof of principle of the applicability of gas phase XAS technique to titanium and titanium oxide, hydride and hydrate systems. Experiments are performed by coupling a pulsed microplasma cluster source (PMCS) with a third generation synchrotron light source, and measuring the intensity of the electron yield coming from the interaction of VUV photons with the clusters seeded in a supersonic beam.