Publications

Abstract Phenolic compounds constitute a diverse group of secondary metabolites which are present in both grapes and wine. The phenolic content and composition of grape processed products (wine) is greatly influenced by the technological practice to which grapes are exposed. During the handling and maturation of the grapes several chemical changes may occur with the appearance of new compounds and/or disappearance of others, and consequent modification of the characteristic ratios of the total phenolic content as well as of their qualitative and quantitative profile. The non-volatile phenolic composition of grapes and wines, the biosynthetic relationships between these compounds, and the most relevant chemical changes occurring during processing and storage will be highlighted in the present study.

Abstract Long chain alkyl hydroxycinnamates (8-21) were synthesized from the corresponding half esters of malonic acid (5-7) and benzaldehyde derivatives by Knoevenagel condensation. The total antioxidant capacity of these hydroxycinnamyl esters was evaluated using DPPH and ABTS assays. The observed antioxidant activity was highest for esters of caffeic acid followed by sinapic esters and ferulic esters. The parameters for drug-likeness of these hydroxycinnamyl esters were also evaluated according to the Lipinski's 'rule-of-five'. All the ester derivatives were found to violate one of the Lipinski's parameters (cLogP >5), even though they have been found to be soluble in protic solvents. The predictive topological polar surface area (TPSA) data allow concluding that they could have a good capacity for penetrating cell membranes. Therefore, one can propose these novel lipophilic compounds as potential antioxidants for tackling oxidative processes.

Abstract Monoamine oxidase (MAO) is an enzyme, present in mammals in two isoforms MAO-A and MAO-B. These isoforms have a crucial role in neurotransmitters metabolism, representing an attractive drug target in the therapy of neurodegenerative diseases (MAO-B) and depression (MAO-A). In this context, our work has been focused on the discovery of new chemical entities (NCEs) for MAO inhibition, based on the development of chromone carboxamides. Chromone derivatives with a carboxamide function located in position 2- and 3- of the benzo-gamma-pyrone core, (compounds 2-6 and 8-12) were synthesized, with moderate/good yields, by a one-pot condensation reaction using phosphonium salts as coupling reagents. The synthetic compounds were screened towards human MAO isoforms (hMAO) to evaluate their potency and selectivity. The chromone-3-carboxamides show high selectivity to hMAO-B, with compounds 9 and 12 displaying IC50 values at nanomolar range. (C) 2010 Published by Elsevier Ltd.

Abstract ADENOSINE A(3) RECEPTORS: A NEW THERAPEUTIC APPROACH IN CANCER. Cancer is a multi-factorial disease linked with different initiating causes, cofactors and promoters, and several types of cellular damage. Advancing knowledge on the cellular and molecular biology of the processes that regulate cell proliferation, cell differentiation and cellular responses to external signals, has provided a wealth of information about the cancer cell and how it differs from a normal one. These findings make available a number of potential targets for new therapeutic approaches. The Medicinal Chemistry artwork performed so far in the development of selective and potent adenosine receptor A(3) ligands, a current cancer target, will be highlighted in this work.

Abstract Cationic liposomes have been extensively studied from the experimental and theoretical standpoints, motivated both by their fundamental interest and by potential applications in drug delivery and gene therapy. However, a detailed understanding of the nature of interactions within mixed bilayers containing cationic gemini surfactants is still lacking. This work focuses on the structural and dynamic properties of DODAB membranes in the presence of dicationic gemini surfactants. A thermodynamic characterization of the phase transitions in the mixed systems has been carried out by differential scanning calorimetry, while insight into the molecular interactions in the bilayer has been provided by molecular dynamics. For this purpose, variations in the gemini spacer and tail length, as well as in the respective molar fraction, have been included in both experimental and simulation studies. The results indicate that the influence of cationic gemini surfactants upon the thermotropic behavior and degree of order of DODAB structures is controlled by a complex interplay between charge density, conformation and hydrophobic effects, for which a detailed rationale is provided.

Abstract Dicationic alkylammonium bromide gemini surfactants represent a class of amphiphiles potentially effective as skin permeation enhancers. However, only a limited number of studies has been dedicated to the evaluation of the respective cytotoxicity, and none directed to skin irritation endpoints. Supported on a cell viability study, the cytotoxicity of gemini surfactants of variable tail and spacer length was assessed. For this purpose, keratinocyte cells from human skin (NCTC 2544 cell line), frequently used as a model for skin irritation, were employed. The impact of the different gemini surfactants on the permeability and morphology of model vesicles was additionally investigated by measuring the leakage of calcein fluorescent dye and analyzing the NMR spectra of P-31, respectively. Detail on the interaction of gemini molecules with model membranes was also provided by a systematic differential scanning calorimetry (DSC) and molecular dynamics (MD) simulation. An irreversible impact on the viability of the NCTC 2544 cell line was observed for gemini concentrations higher than 25 mM, while no cytotoxicity was found for any of the surfactants in a concentration range up to 10 mM. A higher cytotoxicity was also found for gemini surfactants presenting longer spacer and shorter tails. The same trend was obtained in the calorimetric and permeability studies, with the gemini of longest spacer promoting the highest degree of membrane destabilization. Additional structural and dynamical characterization of the various systems, obtained by P-31 NMR and MD, provide some insight on the relationship between the architecture of gemini surfactants and the respective perturbation mechanism.

Abstract The vapor pressures of condensed phases of methyl p-methylbenzoate and methyl p-(dimethylamino)benzoate were measured in the temperature ranges (269.3 to 357.0) K and (325.0 to 390.4) K, respectively, using a static method. The Knudsen mass-loss effusion technique was also used to study the vapor pressures as function of temperature of the crystals of methyl p-(dimethylamino)benzoate in the pressure range (0.1 to 1) Pa. The results obtained for each compound enabled the determination of the standard molar entropies and enthalpies of sublimation and of vaporization at T = 298.15 K as well as phase diagram representations of the (p,T) experimental data. The temperatures and molar enthalpies of fusion were determined using differential scanning calorimetry and were compared with the values derived 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 substituted benzoic acids were calculated.

Abstract Calorimetric measurements are expected to provide useful data regarding the relative stability of alpha- versus beta-amino acid isomers, which, in turn, may help us to understand why nature chose alpha- instead of beta-amino acids for the formation of the biomolecules that are essential constituents of life on earth. The present study is a combination of the experimental determination of the enthalpy of formation of N-benzyl-beta-alanine, and high-level ab initio calculations of its molecular structure. The experimentally determined standard molar enthalpy of formation of N-benzyl-beta-alanine in gaseous phase at T = 298.15 K is (298.8 +/- 4.8) kJ center dot mol(-1), whereas its G3(MP2)//B3LYP-calculated enthalpy of formation is -303.7 kJ center dot mol(-1). This value is in very good agreement with the experimental one. Although the combustion experiments of N-benzyl-alpha-alanine were unsuccessful, its calculated enthalpy of formation is -310.7 kJ center dot mol(-1); thus, comparison with the corresponding experimental enthalpy of formation of N-benzyl-beta-alanine, -(298.8 +/- 4.8) kJ/mol, is in line with the concept that the more branched amino acid (alpha-alanine) is intrinsically more stable than the linear beta-amino acid, beta-alanine.

Abstract A novel volatile microemulsion formed by the catanionic surfactant hexadecyltrimethylammonium octylsulfonate (TA(16)So(8)), heptane and water has been explored as a template for producing nanoparticles of hydrophobic organic materials. Butylated hydroxytoluene (BHT) was employed as the model hydrophobic substance. First, the oil-in-water microemulsion was formed, containing TA16So8 as the single emulsifier and BHT dispersed in the volatile microphase. Microstructure characterization by self-diffusion NMR revealed that BHT was indeed incorporated into the oil droplets and that the mean diameter of the main droplet population was 30 nm, larger than in the BHT-free microemulsion. Next, a rapid solvent and water removal by freeze drying allowed converting the microemulsion droplets into nanoparticles in the form of a dry, fine powder. This powder was freely dispersible in water to yield a stable suspension of amorphous BHT particles with a mean size of 19 nm and zeta-potential of +37 mV. The solid nanoparticles in the aqueous dispersion were thus smaller than the initial microemulsion droplets. For comparison, a conventional o/w microemulsion composed of CTAB and sec-butanol was also tested as a template for BHT particle formation by the same process, and it was found that it yielded crystalline particles of micrometre size. On the basis of our results, we anticipate the catanionic microemulsion method to be an efficient one for producing size-controlled, water-dispersible nanoparticles of other hydrophobic organic materials.