Publications

Abstract Computational methods for Target Fishing (TF), also known as Target Prediction or Polypharmacology Prediction, can be used to discover new targets for small-molecule drugs. This may result in repositioning the drug in a new indication or improving our current understanding of its efficacy and side effects. While there is a substantial body of research on TF methods, there is still a need to improve their validation, which is often limited to a small part of the available targets and not easily interpretable by the user. Here we discuss how target-centric TF methods are inherently limited by the number of targets that can possibly predict (this number is by construction much larger in ligand-centric techniques). We also propose a new benchmark to validate TF methods, which is particularly suited to analyse how predictive performance varies with the query molecule. On average over approved drugs, we estimate that only five predicted targets will have to be tested to find two true targets with submicromolar potency (a strong variability in performance is however observed). In addition, we find that an approved drug has currently an average of eight known targets, which reinforces the notion that polypharmacology is a common and strong event. Furthermore, with the assistance of a control group of randomly-selected molecules, we show that the targets of approved drugs are generally harder to predict. © 2016 Peón, Dang and Ballester.

Abstract A sensitive electrochemical sensor was successfully developed based on a glassy carbon (GC) electrode modified by a combination of multi-walled carbon nanotubes (MWCNT) with beta-cyclodextrin (beta-CD) incorporated in a polyaniline film, and applied to detect and determine the fungicide pyrimethanil in pome fruit (apples). The beta-CD/MWCNT modified GC electrode displayed a detection limit of 1.04 mu M (0.21 mg/kg) which is below the maximum residue levels set for pyrimethanil in pome fruit and citrus fruit by EU regulations. The results indicate that the (beta-CD/MWCNT modified GC electrode exhibits efficient electrocatalytic oxidation of pyrimethanil with high reproducibility, repeatability and stability. Furthermore, the obtained results were in excellent agreement with those obtained using an established HPLC procedure.

Abstract Different kinds of molecularly imprinted particles were synthesized and compared, aiming at the development of materials combining high molecular recognition capabilities and facile use as column packing materials for chromatographic aqueous applications. Solution, inverse-suspension and precipitation polymerization were considered and two different model molecules (5-fluorouracil and caffeine) were used to highlight the effect of the interaction between the template molecule and the functional monomer on imprinting efficiency. Particles synthesized through the proposed inverse-suspension process exhibit facile use for packing columns, allow the stable running of chromatographic systems and present a high performance in drug uptake and release in aqueous media. Frontal analysis measurements highlight these key features of the synthesized particles. Drug sorption capabilities of 0.890 mu mol/g and 5.774 mu mol/g were measured for 5-fluorouracil and caffeine, respectively, using frontal analysis with eluents containing the target molecules at concentration 0.1 mM. Due to the lower amount of solvent required than with precipitation polymerization, the developed inverse-suspension process presents high synthesis yields, which can be exploited for the large-scale manufacture and commercialization of molecularly imprinted materials. The combined features of the particles makes possible their direct use in bioseparations or in the development of assays and pharmacokinetic studies concerning the presence of drugs in biological fluids.

Abstract Novel results concerning the inverse vulcanization of sulfur using reversible addition-fragmentation chain transfer (RAFT) polymerization are here reported. It is shown that RAFT polymerization can be used to carry out this crosslinking process, with the additional possibility to extend the reaction time from a few minutes as with classical free radical polymerization (FRP) to several hours. Higher control on viscosity and processability of the synthesized networks, as well as, the implementation of semibatch feed policies during crosslinking are important advantages of the RAFT process here explored comparatively to the FRP inverse vulcanization. Using cyclic voltammetry, it was assessed the electrochemical activity of the synthesized sulfur-rich polymer networks. It is shown that the fundamental electrochemical activity of the elemental sulfur was preserved in the produced materials. Testing of electrochemical cells assembled with lithium in the anode and different sulfur based materials in the cathode, including the synthesized RAFT networks, is also shown. The results here presented highlight the new opportunities introduced by reversible-deactivation radical polymerization mechanisms on the control of the synthesis process and in the design of such advanced materials and show also that many potential derivatizing possibilities can be achieved. (c) 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016, 133, 43993.

Abstract In the present study, aqueous solutions of a thermo-responsive negatively charged triblock copolymer methoxy-poly(ethylene glycol)-block-poly(N-isopropylacrylamide)-block-poly (2-succinic acid-propyloxyl methacrylate) (MPEG(45)-b-PNIPAAM(48)-b-PSAPMA(10)), have been characterized in the presence of sodium dodecyl sulfate (SDS) or dodecyltrimethylammonium bromide (DTAB) surfactant, at a constant concentration of polymer and various levels of surfactant addition. For this purpose, dynamic light scattering (DLS) was used to probe the effect of the ionic surfactants on the size of the block copolymer species, and small angle neutron scattering (SANS) was applied as a complementary technique to probe the structure on a mesoscopic length scale. The results obtained revealed that the addition of a surfactant to the copolymer solution leads to a decrease of the particle size, due to electrostatic repulsions and solubilization of the hydrophobic microdomains. By zeta potential analysis it was shown that the charge density of the surfactant-coated polymer moieties increases with increasing surfactant concentration. The turbidities of the polymer-surfactant mixtures were measured using a cloud point analyzer. Our data revealed that the behavior not only depends on the surfactant concentration, but it is also affected in some cases by temperature. In addition, cytotoxicity studies were carried out on mouse fibroblasts cells NIH-3T3 to evaluate the potential of the systems as drug delivery carriers. Results showed that the cytotoxicity of the polymer changes with surfactant addition, rising as the concentration of SDS increases but falling off with increasing DTAB concentration.

Abstract Glioblastoma (GBM), the highest grade astrocytoma, is one of the most aggressive and challenging cancers to treat. The standard treatment is usually limited due to the intrinsic resistance of GBM to chemotherapy and drug non-specific effects. Therefore, new therapeutic strategies need to be developed to target tumor cells, sparing healthy tissues. In this context, the inhibitor-of-apoptosis protein (IAP) survivin emerges as an ideal target for a gene silencing approach, since it is sharply differentially expressed in cancer tissues. In this work, two different families of cationic gemini surfactants (bis-quat conventional and serine-derived) were tested regarding their efficiency to deliver small interfering RNAs (siRNAs) in a human GBM cell line (U87), in order to select an effective siRNA anti-survivin carrier. Importantly, survivin downregulation combined with administration of the chemotherapeutic agents temozolomide or etoposide resulted in a synergistic cytotoxic effect, thus revealing to be a promising strategy to reduce the chemotherapeutic doses for GBM treatment.

Abstract This paper reports experimental vapor pressures of condensed phases of methyl p-cyano, p-formyl, p-nitro, and p-(methylamino) benzoates measured over the temperature ranges (303.9 to 393.0) K, (303.1 to 388.2) K, (319.0 to 415.8) K, and (332.9 to 392.4) K, respectively, using a static method based on capacitance diaphragm manometers. The Knudsen mass-loss effusion technique was also used to measure the vapor pressures of crystalline methyl p-(methylamino)benzoate in the temperature range (317.1 to 339.2)" K. These results enabled the calculation of the standard molar enthalpies and entropies of sublimation and of vaporization, at reference temperatures as well as the (p,T) values of the triple point of each compound. The temperatures and molar enthalpies of fusion were determined using differential scanning calorimetry and were compared with the values derived indirectly from the vapor pressure measurements. The enthalpies of the intermolecular hydrogen bonds O-H center dot center dot center dot O in the crystalline phase of the parent benzoic acids were determined.

Abstract This work reports the experimental determination of relevant thermodynamic properties and the characterization of luminescence properties of the following polycyclic aromatic hydrocarbons (PAHs): 2,6-diethylnaphthalene, 2,6-diisopropylnaphthalene and 2,6-di-tert-butylnaphthalene. The standard (p(o) = 0.1 MPa) molar enthalpies of combustion, Delta H-c(m)o, of the three compounds were determined using static bomb combustion calorimetry. The vapor pressures of the crystalline phase of 2,6-diisopropylnaphthalene and 2,6-di-tert-butylnaphthalene were measured at different temperatures using the Knudsen effusion method and the vapor pressures of both liquid and crystalline phases of 2,6-diethylnaphthalene were measured by means of a static method. The temperatures and the molar enthalpies of fusion of the three compounds were determined using differential scanning calorimetry. The gas-phase molar heat capacities and absolute entropies of the three 2,6-dialkylnaphthalenes studied were determined computationally. The thermodynamic stability of the compounds in both the crystalline and gaseous phases was evaluated by the determination of the Gibbs energies of formation and compared with the ones reported in the literature for 2,6-dimethylnaphthalene. From fluorescence spectroscopy measurements, the optical properties of the compounds studied and of naphthalene were evaluated in solution and in the solid state.

Abstract This work presents a comprehensive experimental and computational study of the thermodynamic properties of 2,7-di-tert-butylfluorene. The standard (p(o) = 0.1 MPa) molar enthalpy of formation in the crystalline phase was derived from the standard molar energy of combustion, measured by static bomb combustion calorimetry. The enthalpies and temperatures of transition between condensed phases were determined from DSC experiments. The vapour pressures of the crystalline and liquid phases were measured between (349.14 and 404.04) K, using two different experimental methods. From these results the standard molar enthalpies, entropies and Gibbs energies of sublimation and of vaporization were derived. The enthalpy of sublimation was also determined using Calvet microcalorimetry. The thermodynamic stability of 2,7-di-tert-butylfluorene in the crystalline and gaseous phases was evaluated by the determination of the standard Gibbs energies of formation, at the temperature 298.15 K, and compared with the ones reported in the literature for fluorene. A computational study at the G3(MP2)//B3LYP and G3 levels has been carried out. A conformational analysis has been performed and the enthalpy of formation of 2,7-di-tert-butylfluorene has been calculated, using atomization and isodesmic reactions. The calculated enthalpies of formation have been compared to the experimental values. (C) 2016 Elsevier Ltd.

Abstract The current work addresses a thermochemical study regarding the compounds N-methylphenothiazine and N-methylphenoxazine. The excellent agreement between the experimental and computational gas-phase enthalpy of formation values obtained for the N-methylphenothiazine reinforced the validation/ calibration of the computational methodology established, allowing the use of it for the homologous oxygen derivative. The computational studies were also extended to the attainment of gas-phase molar heat capacities at different temperatures, dipole moment, electrostatic potential energy maps mapped onto electron density isosurface, and frontier orbitals of N-methylphenothiazine and N-methylphenoxazine. The experimental techniques used were the Knudsen mass-loss effusion, Calvet microcalorimetry and combustion calorimetry aiming, respectively, the determination of the temperature-vapour pressures dependences, the enthalpy of sublimation and the massic energy of combustion of N-methylphenothiazine. These quantities were used to derive the corresponding enthalpy of formation in the gas phase, at T = 298.15 K, (271.3 +/- 4.1) kJ . mol(-1). The results obtained for the enthalpies of formation are discussed and compared with related compounds, providing an opportunity to evaluate the effects in the enthalpies of formation associated with the substitution of the hydrogen of the amino group by a methyl group.