Exploring Mannosylpurines as Copper Chelators and Cholinesterase Inhibitors with Potential for Alzheimer's Disease.

Alzheimer's Disease (AD) is characterized by a progressive cholinergic neurotransmission imbalance, with a decrease of acetylcholinesterase (AChE) activity followed by a significant increase of butyrylcholinesterase (BChE) in the later AD stages. BChE activity is also crucial for the development of Aß plaques, the main hallmarks of this pathology. Moreover, systemic copper dyshomeostasis alters neurotransmission leading to AD. In the search for structures targeting both events, a set of novel 6-benzamide purine nucleosides was synthesized, differing in glycone configuration and N7/N9 linkage to the purine. Their AChE/BChE inhibitory activity and metal ion chelating properties were evaluated. Selectivity for human BChE inhibition required N9-linked 6-deoxy-α-d-mannosylpurine structure, while all three tested ß-d-derivatives appeared as non-selective inhibitors. The N9-linked l-nucleosides were cholinesterase inhibitors except the one embodying either the acetylated sugar or the N-benzyl-protected nucleobase. These findings highlight that sugar-enriched molecular entities can tune bioactivity and selectivity against cholinesterases. In addition, selective copper chelating properties over zinc, aluminum, and iron were found for the benzyl and acetyl-protected 6-deoxy-α-l-mannosyl N9-linked purine nucleosides. Computational studies highlight molecular conformations and the chelating molecular site. The first dual target compounds were disclosed with the perspective of generating drug candidates by improving water solubility.

Generation of naphthoquinone radical anions by electrospray ionization: solution, gas-phase, and computational chemistry studies.

Radical anions are present in several chemical processes, and understanding the reactivity of these species may be described by their thermodynamic properties. Over the last years, the formation of radical ions in the gas phase has been an important issue concerning electrospray ionization mass spectrometry studies. In this work, we report on the generation of radical anions of quinonoid compounds (Q) by electrospray ionization mass spectrometry. The balance between radical anion formation and the deprotonated molecule is also analyzed by influence of the experimental parameters (gas-phase acidity, electron affinity, and reduction potential) and solvent system employed. The gas-phase parameters for formation of radical species and deprotonated species were achieved on the basis of computational thermochemistry. The solution effects on the formation of radical anion (Q(•-)) and dianion (Q(2-)) were evaluated on the basis of cyclic voltammetry analysis and the reduction potentials compared with calculated electron affinities. The occurrence of unexpected ions [Q+15](-) was described as being a reaction between the solvent system and the radical anion, Q(•-). The gas-phase chemistry of the electrosprayed radical anions was obtained by collisional-induced dissociation and compared to the relative energy calculations. These results are important for understanding the formation and reactivity of radical anions and to establish their correlation with the reducing properties by electrospray ionization analyses.

Application of the atoms in molecules theory and computational chemistry in mass spectrometry analysis of 1,4-naphthoquinone derivatives.

Mass spectrometry analysis of 2-(acylamino)-1,4-naphthoquinone derivatives was carried out using electrospray ionization ion source in combination with tandem mass spectrometry. Protonated molecules were dissociated by application of the collision-induced dissociation (CID), and the protonation sites were suggested on the basis of the HOMO, molecular electrostatic potential map (MEP), proton affinity, and Fukui functions calculated by B3LYP/6-31+G(d,p). The main fragmentation mechanisms undergone by the protonated ions were elucidated on the basis of energy, geometry, and topology analysis of equilibrium geometries. Compounds exhibiting only aliphatic hydrogens at the lateral chain undergo interesting ketene elimination. On the other hand, only the benzoylium ion formation is detected for 2-benzoylamino-1,4-naphthoquinone. The bonds geometric and atoms in molecules parameters give evidence that acidic hydrogen atoms play an important role in the fragmentation pathways.

Fragmentation studies of synthetic 2-acylamino-1,4-naphthoquinones by electrospray ionization mass spectrometry.

We report here the fragmentation mechanism for five 2-acylamino-1,4-naphthoquinone derivatives using electrospray ionization tandem mass spectrometry (ESI-MS/MS). Analyses were performed on a low-resolution, triple-quadrupole mass spectrometer. Fragmentation pathways for protonated molecular derivatives 2-acylamino-1,4-naphthoquinone [M+H]+ are proposed on the basis of theoretical calculations. There is evidence that the nitrogen atom is the protonation site, based on the nucleophilic atomic indices.

Pharmacokinetic disposition of erythraline in rats after intravenous administration

ABSTRACT Erythraline is the major alkaloid produced by Erythrina verna Vell., Fabaceae, a plant used in folk medicine and phytotherapeutic products to treat anxiety and sleep disorders. This study aimed to investigate the pharmacokinetic parameters of erythraline after intravenous administration in rats. For the analysis of erythraline in rat plasma, a method was developed and validated using UHPLC-MS/MS. Pharmacokinetic parameters were estimated by non-compartmental analysis. The metabolite 8-oxo-erythraline observed in previous biomimetic model studies was monitored during in vivo experiments. The quantification limit was 5 ng/ml within a linear range of 5-2000 ng/ml. After an intravenous dose of 1 mg/kg, the following pharmacokinetic parameters were observed: elimination half-life of 44.2 min; total clearance of 42.1 ml/min/kg and volume of distribution of 2085 ml/kg. In summary, a precise, accurate and selective UHPLC-MS/MS method was developed and successfully applied to investigate the pharmacokinetics of erythraline in rats. The metabolite 8-oxo-erythraline was observed in rat plasma after 20 min of erythraline administration.

Gas-phase dissociation of 1,4-naphthoquinone derivative anions by electrospray ionization tandem mass spectrometry.

Gas-phase dissociation pathways of deprotonated 1,4-naphthoquinone (NQ) derivatives have been investigated by electrospray ionization tandem mass spectrometry (ESI-MS/MS). The major decomposition routes have been elucidated on the basis of quantum chemical calculations at the B3LYP/6-31 + G(d,p) level. Deprotonation sites have been indicated by analysis of natural charges and gas-phase acidity. NQ anions underwent an interesting reaction under collision-induced dissociation conditions, which resulted in the radical elimination of the lateral chain, in contrast with the even-electron rule. Possible pathways have been suggested, and their mechanisms have been elucidated on the basis of Gibbs energy and enthalpy values for the anions previously described at each pathway.