Publications

Abstract Background: Due to the complex etiology of neurodegenerative diseases, there is growing interest in multitarget drugs. In this study we synthesized and evaluated a new series of compounds, with benzo[f]coumarin structure, as potential inhibitors of MAO-A, MAO-B, AChE and BuChE. Results:In vitro studies show that most of the studied compounds inhibited the activity of MAO-B in the nano- to micro-molar range. 3-(3 '-methoxyphenyl)benzo[f]coumarin is the most active compound with an IC50 value against MAO-B of 2.44 nM. Most of the derivatives exhibited an important selectivity profile against the MAO-B isoform. Some of them also acted as in vitro inhibitors of BuChE, with 3-(2 '-hydroxyphenyl)benzo[f]coumarin being the most active with an IC50 value of 1.13 mu M. In addition, a theoretical study of the physicochemical properties of the new compounds, as well as a docking study in both MAO isoforms, were carried out. Important structure-activity relationships were obtained. Conclusion: Important preliminary structure-activity relationships were concluded from the experimental results. These results encourage us to further explore the potential of this chemical family as potential drug candidates for the treatment of Alzheimers disease.

Abstract AsLn2, an unusual modified peptide, was isolated from the bioluminescent earthworm Fridericia heliota (Enchytraeidae). Its structure, elucidated by NMR and mass spectrometry, includes residues of tyrosine, CompX (a novel tyrosine modification product, reported in the accompanying paper), and N(omega)-acylated lysine. Chromatography, UV, and H-1 NMR data imply a close structural similarity of AsLn2 with F. heliota luciferin. AsLn2 appears to be an intermediate or by-product in F. heliota luciferin biosynthesis.

Abstract A luciferin analog, CompX, was isolated from the extracts of the bioluminescent earthworm Fridericia heliota. Its structure was determined as (Z)-5-(2-carboxy-2-methoxyvinyl)-2-hydroxybenzoic acid by spectroscopic data analysis and was confirmed by total synthesis. The (Z)-configuration of the double bond was established by comparing the ROESY spectra of CompX with those of its synthetic (E)-isomer. CompX represents a tyrosine analog, not previously found in natural sources, and is probably derived from tyrosine by deamination, O-methylation of the resulting alpha-keto acid, and carboxylation at the aromatic core.

Abstract The aim of this study is to investigate the efficacy of new, biocompatible, lysine-based surfactants as chemical permeation enhancers for two different local anesthetics, tetracaine and ropivacaine hydrochloride, topically administered. Results show that this class of surfactants strongly influences permeation, especially in the case of the hydrophilic and ionized drug, ropivacaine hydrochloride, that is not easily administered through the stratum corneum. It is also seen that the selected permeation enhancers do not have significant deleterious effects on the skin structure. A cytotoxicity profile for each compound was established from cytotoxicity studies. Molecular dynamics simulation results provided a rationale for the experimental observations, introducing a mechanistic view of the action of the surfactants molecules upon lipid membranes.

Abstract Luminescent carbon-based nanoparticles, addressed as carbon dots (CDs), were synthesized at relatively low temperature from lactose following an easy and inexpensive procedure. Modification of their surface was done by functionalization with mercaptosuccinic acid (MSA) (CDs-MSA). Transmission electron microscopy images showed regular spherical nanoparticles of 5 nm diameter. Raw and functionalized (CDs-MSA) CDs were highly fluorescent at 448 and 472 nm, with relative high quantum yield (Phi = 0.21 and 0.46 respectively). At the maximum fluorescence of CDs-MSA the intensity was quenched by addition of Ag+ ions by a static mechanism with a Stern-Volmer constant of 3.7 x 10(3) M-1. The analysis of the emission spectra showed that the CD-MSA complex was stable after this process. The quenching profiles showed that only 44% of the CD-MSA fluorophores are accessible to Ag+. The main figures of merit were detection and quantification limits of 385.8 nM and 1.2 mu M respectively, and the precision as relative standard deviation was 1.76%. No interference was observed when other metal ions were present indicating a high selectivity for Ag+ detection. The results showed that CDs-MSA can be used for efficient quantification of Ag+ in silver nanoparticle dissolution.

Abstract An enthalpic value for the N-methyllactam/O-methyllactim isomerization, in the gaseous phase, is reported in this work for the conversion between 2,4-dimethoxypyrimidine and 1,3-dimethyluracil. For this purpose, the enthalpy of formation of 2,4-dimethoxypyrimidine, in the gaseous phase, was obtained experimentally combining results from combustion calorimetry and Calvet microcalorimetry, and the enthalpy of formation of 1,3-dimethyluracil, in the gaseous phase, reported previously in the literature, is also discussed. The enthalpy of hydrogenation of 1,3-dimethyluracil is compared with the enthalpy of hydrogenation of uracil and interpreted in terms of aromaticity, considering the influence of the hyperconjugation and the hindrance of the solvation of the ring by the methyl groups. The enthalpy of sublimation of 2,4-dimethoxypyrimidine was obtained combining Calvet microcalorimetry and differential scanning calorimetry results. This enthalpy is compared with the enthalpy of sublimation of 1,3-dimethyluracil previously reported in the literature and analyzed herein. From the interplay between the experimental results and the theoretical simulation of dimers of these molecules, the influence of stereochemical hindrance on the in-plane intermolecular contacts and aromaticity on the pi center dot center dot center dot pi interactions is analyzed.

Abstract 4(3H)-Pyrimidinone is observed in nature in equilibrium with other tautomeric forms, mimicking the tautomeric equilibrium in pyrimidine nucleobases. In this work, the enthalpy of formation in the gaseous phase of 4(3H)-pyrimidinone was derived from the combination of the enthalpy of formation in the crystalline phase, obtained by static bomb combustion calorimetry, and the enthalpy of sublimation, obtained by Knudsen effusion. The gaseous phase enthalpy of formation of 4(3H)-pyrimidinone was interpreted in terms of isodesmic reactions that consider the enthalpic effects of hydroxypyridines and pyrimidine. After comparison of the experimental and computational results, the same type of isodesmic reactions was used to study the substituent effects of the hydroxyl functional group of 2-, 4-, and 5-hydroxypyrimidines. The influence of aromaticity on the energetics of hydroxypyrimidines was evaluated using the variation of nucleus-independent chemical shifts for several reactions. The influence of intramolecular hydrogen bonds was investigated using the quantum theory of atoms in molecules and the geometric rule of Baker and Hubbard to identify hydrogen bonds. The energetic results obtained were also interpreted in terms of an in plane anomeric effect in the pyrimidine ring.

Abstract The enthalpy of formation of indigo, as a solid, was reported in 1893. The enthalpy of sublimation at a mean temperature of 577 K (ca. 298 degrees C) was reported some 90 years later, and corrected herein to 298 K. These values were summed to result in a standard gas phase enthalpy of formation. We have also performed quantum chemical calculations at the B3LYP/6-311++ G(d, p) level and analyzed them using (not quite) isodesmic and isomerisation reactions. From these disparate calorimetric and computational approaches, we hereby present a recommended enthalpy of formation of gaseous indigo of (35 +/- 16) kJ.mol (1).