Tamoxifen derivatives for delivery of the antitumoral (DACH)Pt group: selective synthesis by McMurry coupling,and biochemical behaviour

The goal of our study was to potentiate the effects of the ((R,R)-trans-1,2-diaminocyclohexane)-platinum(II) fragment [(DACH)Pt], known for its cytotoxic properties, either with tamoxifen (Tam), the most widely used antiestrogen in the treatment of hormone-dependent breast cancers, or with its active metabolite hydroxytamoxifen (hydroxy-Tam). We coupled Tam or hydroxy-Tam derivatives bearing a malonato group at the para position of the beta aromatic ring with the (DACH)Pt fragment. The malonato-Tam and malonato-hydroxy-Tam compounds were prepared through McMurry coupling of the appropriate ketones. The presence of the malonate group resulted in a pronounced stereospecificity in the reaction, since malonato-Tam was obtained only as the Z isomer, while malonato-hydroxy-Tam was obtained as an 80/20 E/Z mixture. Attribution of the isomeric structures was achieved by 2D NMR spectroscopy. The platinum complexes (DACH)Pt-malonato-Tam and (DACH)Pt-malonato-hydroxy-Tam were then prepared by coupling the barium salts derived from the malonato-Tam and malonato-hydroxy-Tam with the nitrate derived from (DACH)PtCl(2). Study of the biochemical properties of these two platinum complexes showed that, while the hydroxy-Tam complex is satisfactorily recognized by the estrogen receptor (relative binding affinity, RBA=6.4 %), the Tam complex is less well recognized (RBA=0.5 %). The effects of these complexes on two hormone-dependent breast cancer cell lines (MCF7 and MVLN) were studied in vitro. Both complexes showed an antiproliferative effect on MCF7 cells, and an antiestrogenic effect on MVLN cells. The observed effects appear to be essentially antihormonal, since incorporation of the (DACH)Pt fragment into the tamoxifen skeleton did not cause an increase in the cytotoxicity of the complexes.     

Synthesis and Pharmacological Evaluation of a series of the Agomelatine Analogues as Melatonin MT1/MT2 Agonist and 5‐HT2C Antagonist

Agomelatine is a naphthalenic analogue of melatonin that is in clinical use for the treatment of major depressive disorders. Interestingly, while agomelatine exhibits potent affinity for melatonin receptors, it binds with only moderate affinity to the serotonin 5‐HT_2C receptor. Optimization of agomelatine toward this target could further potentiate its clinical efficacy. To explore this hypothesis and to access derivatives in which a key point of agomelatine metabolism is blocked, a series of naphthalenic derivatives was designed and synthesized as novel analogues of agomelatine. Most of the prepared compounds exhibited good binding affinity at the melatonin MT₁ and MT₂ receptor subtypes. Two compounds, an acetamide and an acrylamide derivative, exhibited good binding affinities at both the human melatonin (MT) receptors and the serotonin 5‐HT_2C receptor subtype, with pK_i values of 7.96 and 7.95 against MT₁, 7.86 and 8.68 against MT2, and 6.64 and 6.44 against 5‐HT_2C, respectively.     

Multilayer films ageing under ultraviolet radiations: Complementary study by dielectric spectroscopy

The effect of ultraviolet (UV) irradiation on a multilayer film made of poly(ethylene terephthalate)/Polyamide 6/poly(ethylene terephthalate) was investigated by uniaxial tractions, UV‐visible‐NIR and Fourier transformed infra‐red‐attenuated total reflection spectroscopy, differential scanning calorimetry ( DSC), and dynamic dielectric spectroscopy (DDS). The multilayer was exposed to ultraviolet radiations (filtered at 270 nm) for 7 days, in air. The complexity of the multilayer thermograms recorded by DSC and DDS has required the study of each film constituting the multilayer to assess each the contribution of each one of them. A deterioration in mechanical properties and a decrease in UV transmission for low wavelengths are observed. These evolutions seem to result to the photo‐oxidation of the poly(ethylene terephthalate) film mainly localized at the exposed layer. This layer acts as a UV protection filter for the other layers. However, the DDS analyses show a plasticization effect of the primary mode in the Polyamide 6, which is evidence of photo‐oxidation. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

Polymer stain resistance: Prediction versus experiment

The coloration of different polymer films (from commodity and packaging films to performance films) by contact with various food coloring substances was evaluated. For this purpose, both solubility parameters as a prediction tool, and immersion experiments for time range between 24 and 1000 h were established. The two predicting tools are the Hoy and Hoftyzer‐Van Krevelen (HVK) methods. For PE and PP, HVK's method is preferred for predicting coloration. Neither of the HVK's and Hoy's methods was able to establish a coloration prediction for PET while both methods could predict the staining of PEEK. The coloration of partially and fully fluorinated polymers is well predicted by the Hoy's method. The behavior of PP/PA and PP/PA/PP multilayer films was also studied. Crystallinity degree of polymers, temperature and concentration of coloring molecules are also important parameters, which are not taken into account in solubility theories. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

Phase Separation and Spatial Morphology in Sodium Silicate Glasses by AFM,Light Scattering and NMR

The morphological and structural properties of sodium silicate (Na₂O–SiO₂) glasses were analyzed using atomic force microscopy (AFM) and light scattering following thermal treatments. AFM observations indicated that the glass surface microstructure evolves during the phase separation mechanisms from continuous interpenetrating phases in the spinodal decomposition process to separated droplets embedded in a continuous matrix for the nucleation/growth one. Raman mapping gave evidence of a phase separation through the nucleation/growth process with formation of silica‐rich clusters characterized by higher polymerization degree as separate droplets. The variations in inhomogeneities versus temperature investigated by Brillouin are exponential for spinodal decomposition and linear in the case of nucleation/growth mechanism. Nuclear magnetic resonance spectroscopy was used to investigate the spatial distribution of the various Q_n species present in thermally treated glasses and allows determining fractal dimension between two and three.     

Interlaboratory Test of Exhaust PM Using ELPI

Abstract

The Particulate Measurement Programme (PMP) works on the development of an improved method for the exhaust particulate matter (PM) measurement, which can include, if feasible and necessary, the measurement of particle number. The French PMP subgroup, composed of IFP, PSA Peugeot-Citroën, Renault, and UTAC, has defined a measurement protocol based on electrical low-pressure impactor (ELPI) and conducted an interlaboratory test to evaluate its performances. The technical program was based on tests carried out on three Euro3 passenger cars (one gasoline operating under stoichiometric conditions, one Diesel, and one Diesel equipped with a diesel particulate filter (DPF)) that were tested on the New European Driving Cycle (NEDC). The regulated pollutants are also measured, as indicators of test repeatability and good working conditions. The interlaboratory reproducibility value of the tunnel background tests is quite high (337%) due to low particle numbers. The repeatability values increase at low particle numbers independently of the vehicle used. On the NEDC, the reproducibility of total particle number is 59, 47, and 131% for the gasoline, Diesel, and DPF-equipped Diesel vehicles, respectively (compare to 67, 29, and 164% for PM collected on filters). These results show that the protocol used in this study allows a reliable measurement of exhaust particle number in the case of vehicles emitting at least two orders of magnitude more than the tunnel background. In the other cases, the measurement variability is too high, especially for regulatory purposes, without taking into account other metrological aspects, such as calibration.     

An Interactive Tool for the Optimization of Freeze-Drying Cycles Based on Quality Criteria

Among existing dehydration methods, freeze-drying has unique benefits for the stabilization and preservation of biological activity of pharmaceutical products but remains an expensive and time-consuming process. A user-friendly software tool was developed, allowing for interactive selection of process operating condition profiles in order to maximize process productivity while insuring product quality preservation. The software is based on a dynamic, one-dimensional heat and mass transfer model, which can accurately represent both the primary and secondary drying stages and the gradual transition between them. The model was validated in a wide range of operating conditions: ? 25 to + 25°C shelf temperature and 10 to 34 Pa total pressure. By comparing a reference sucrose solution with a formulated pharmaceutical product containing polyvinylpyrrolidone (PVP), it is shown that controlling product properties such as glass transition temperature and sorption isotherm can reduce the minimum achievable cycle duration by 12 h (33%).     

When NHC Ligands Make a Difference in Gold Catalysis

Thanks to their unique electronic and steric properties, carbene ligands offer highly valuable features for catalysis, including homogenous gold catalysis. The use of carbene-gold complexes has improved existing reactions, either by modifying reactivity modes or by leading to highly asymmetric processes. These topics will be discussed on the basis of selected examples.     

N,N′-alkylated Imidazolium-Derivatives Act as Quorum-Sensing Inhibitors Targeting the Pectobacterium atrosepticum-Induced Symptoms on Potato Tubers

Bacteria belonging to the Pectobacterium genus are the causative agents of the blackleg and soft-rot diseases that affect potato plants and tubers worldwide. In Pectobacterium, the expression of the virulence genes is controlled by quorum-sensing (QS) and N-acylhomoserine lactones (AHLs). In this work, we screened a chemical library of QS-inhibitors (QSIs) and AHL-analogs to find novel QSIs targeting the virulence of Pectobacterium. Four N,N′-bisalkylated imidazolium salts were identified as QSIs; they were active at the μM range. In potato tuber assays, two of them were able to decrease the severity of the symptoms provoked by P. atrosepticum. This work extends the range of the QSIs acting on the Pectobacterium-induced soft-rot disease.