Publications

Abstract Coelenterazine is a widespread bioluminescent substrate for a diverse set of marine species. Moreover, its imidazopyrazinone core is present in eight phyla of bioluminescent organisms. Given their very attractive intrinsic properties, these bioluminescent systems have been used in bioimaging, photodynamic therapy of cancer, as gene reporter and in sensing applications, among others. While it is known that bioluminescence results from the thermolysis of high-energy dioxetanones, the mechanism and dioxetanone species responsible for the singlet chemiexcitation of Coelenterazine are not fully understood. The theoretical characterization of the reactions of model Coelenterazine dioxetanones showed that efficient chemiexcitation is caused by a neutral dioxetanone with limited electron and charge transfer, by accessing a region of the PES where ground and excited states are nearly-degenerated. This finding was supported by calculation of equilibrium constants, which showed that only neutral dioxetanone is present in conditions associated with bioluminescence. Moreover, while cationic amino acids easily protonate amide dioxetanone, anionic ones cannot deprotonate the neutral species. These results indicate that, contrary to existent theories, efficient chemiexcitation can occur with significant electron and/or charge transfer. In fact, these processes can be prejudicial to chemiexcitation, as anionic dioxetanones showed a less efficient chemiexcitation despite the occurrence of significant electron and charge transfer.

Abstract The ring-opening reaction of epoxides is a key step in the conversion of carbon dioxide (CO2), a greenhouse waste product of fossil fuel combustion, into value-added heterocyclic carbonates. Being an essential step in CO2 conversion, controlling its activation energy is essential in the development of methods in which heterocyclic carbonates can be obtained under mild conditions. We have employed a theoretical approach to obtain mechanistic insight into the ring-opening of a model epoxide, when catalyzed by both 2,6-phenylboronic acids and pyridinic bases. The presence of both catalysts decreases the activation energy of this process from similar to 60 to similar to 20 kcal mol(-1). The electronic character of the substituent at the C-2,C-6-position of phenylboronic acid has little effect on the activation energy. Nevertheless, electron-withdrawing substituents decrease the activation energy by increasing the acidity of the boronic acid group. It was also found that nonhalogenated pyridinic bases present similar results to those provided by halide nucleophiles. Thus, two-component systems composed by phenylboronic acids and pyridinic bases appear to be a good choice for catalyzing the ring opening reaction of epoxides under mild, metal-free, and nonhalogenated conditions.

Abstract In this study, following a systematic approach, we used aquatic species (bacteria Vibrio fischeri and microalgae Raphidocelis subcapitata) and different human cell lines (Caco-2, HepG2, SV-80 and HaCaT) representing different tissues and exposure pathways, to investigate how two organic stabilizers (PVA and DMSO) used for NMs dispersion influence their physicochemical properties, the persistence of metals in suspension and the toxicity/ecotoxicity of two metallic NMs (nano-Ag and nano-Cu). Although the stabilizers are expected to contribute to improve the dispersion and stability of NMs, the results obtained clearly showed that no similar changes in toxicity and morphological properties of the nano-Ag can be expected after its stabilization with PVA. Thus, regarding human cell lines, the reduction in the average size of the PVA-nano-Ag was followed by a reduction or maintenance of its toxicity, but the opposite was observed for the aquatic species tested since an increase in the average size enhanced its toxicity. As far as nano-Cu is considered DMSO contributed for a better dispersion of this nanomaterial, however this was not translated in a similar toxicity/ecotoxicity modification. In summary, even for nano-Cu, for which few or no data exists regarding its toxicity after stabilization with organic compounds, it was confirmed with consistent data, that the toxicity of metallic NMs is a complex combination of average size, chemical composition, solubilization or persistence in suspension of the metallic forms, interaction with test medium components and sensitivity of test species and cell lines. The combination of all of these factors makes the toxicity of metallic NMs unpredictable and points for the need of an extensive evaluation of each new formulation.

Abstract Compounds of hybrid structure pyridazine-coumarin were discovered as potent, selective and reversible inhibitors of monoamine oxidase B (MAO-B). These compounds were synthesized in good yield following a multistep approach based on Knoevenagel reaction and using as key intermediate pyridazinone 16, which was obtained from maleic anhydride and furan. Compounds 9b and 9d are the most active compounds of these series, with IC50 values in the sub-micromolar range, and lack of cytotoxic effects. Theoretical calculation of ADME properties also suggested a good pharmacokinetic profile for both compounds. Docking simulations provided insights into enzyme inhibitor interactions and allowed us to rationalize the observed structure-activity relationships (SARs).

Abstract In this work we developed a new force field model (FFM) for propylene glycol (PG) based on the OPLS all-atom potential. The OPLS potential was refined using quantum chemical calculations, taking into account the densities and self-diffusion coefficients. The validation of this new FFM was carried out based on a wide range of physicochemical properties, such as density, enthalpy of vaporization, self-diffusion coefficients, isothermal compressibility, surface tension, and shear viscosity. The molecular dynamics (MD) simulations were performed over a large range of temperatures (293.15-373.15 K). The comparison with other force field models, such as OPLS, CHARMM27, and GAFF, revealed a large improvement of the results, allowing a better agreement with experimental data. Specific structural properties (radial distribution functions, hydrogen bonding and spatial distribution functions) were then analyzed in order to support the adequacy of the proposed FFM. Pure propylene glycol forms a continuous phase, displaying no microstructures. It is shown that the developed FFM gives rise to suitable results not only for pure propylene glycol but also for mixtures by testing its behavior for a 50 mol % aqueous propylene glycol solution. Furthermore, it is demonstrated that the addition of water to the PG phase produces a homogeneous solution and that the hydration interactions prevail over the propylene glycol self-association interactions.

Abstract Photodynamic therapy (PDT) is a minimally invasive therapeutic modality for cancer therapy. The main advantage of PDT is its selectivity as it is only activated upon photo-excitation of a photosensitizer by light of selected wavelengths, thereby reducing the number of side effects when compared with other therapies. However, typical photosensitizers absorb strongly UV or visible light, which is generally unsuitable for biological penetration due to light absorption and scattering by tissue. Moreover, the depth of light penetration into the tissues is less than 1 cm. Thus, PDT is usually only used on tumors on or just under the skin or on the outer lining of internal organs/cavities. Moreover, PDT is also ineffective against metastatic tumors, given its localized nature. Therefore, developing ways in which the photosensitizer can be activated inside the cell without an external light source is a challenging and hot research topic, as achieving this goal will increase immensely the role of PDT in routine cancer therapy. In this chapter will be discussed the benefits and pitfalls of using chemi-and bioluminescent systems as intracellular excitation sources in PDT. Bioluminescence is a widespread natural phenomenon, which consists on light emission that results from an oxidation reaction, catalyzed by an enzyme in a biological system. Bioluminescence can be found in fireflies, bacteria, fishes, dinoflagellates and fungi, among others. Bioluminescence can be considered as a sub-type of chemiluminescence, which consists on the chemical production of light as the result of chemical reactions. Given this, these systems can be coupled to the photosensitizer inside tumor cells, thereby creating self-illuminating PDT systems without the problems associated with the use of external light sources. © Nova Science Publishers, Inc.

Abstract Background: Virtual methodologies have become essential components of the drug discovery pipeline. Specifically, structure-based drug design methodologies exploit the 3D structure of molecular targets to discover new drug candidates through molecular docking. Recently, dual target ligands of the Adenosine A2A Receptor and Monoamine Oxidase B enzyme have been proposed as effective therapies for the treatment of Parkinson’s disease. Methods: In this paper we propose a structure-based methodology, which is extensively validated, for the discovery of dual Adenosine A2A Receptor/Monoamine Oxidase B ligands. This methodology involves molecular docking studies against both receptors and the evaluation of different scoring functions fusion strategies for maximizing the initial virtual screening enrichment of known dual ligands. Results: The developed methodology provides high values of enrichment of known ligands, which outperform that of the individual scoring functions. At the same time, the obtained ensemble can be translated in a sequence of steps that should be followed to maximize the enrichment of dual target Adenosine A2A Receptor antagonists and Monoamine Oxidase B inhibitors. Conclusion: Information relative to docking scores to both targets have to be combined for achieving high dual ligands enrichment. Combining the rankings derived from different scoring functions proved to be a valuable strategy for improving the enrichment relative to single scoring function in virtual screening experiments. © 2017 Bentham Science Publishers.

Abstract The detection of dissolved carbon dioxide (dCO(2)) is made possible through a colorimetric effect that occurs in a sensitive membrane. The reaction with dCO(2) changes the pH of the membrane causing a small difference in its colour which results in a characteristic absorbance spectrum band near 435 nm. A sensing platform based on this effect was developed and tested in gaseous and in aqueous environments. It is a combination of a bundle of large core fibre optics (with diameters above 200 mu m) with light emission diodes (LEDs) in the visible range of the spectrum, a silicon photodetector and a polymer membrane sensitive to CO2. A variation in the absorption of 3 / %VV was obtained in the range from 0 to 1.6 % of gaseous CO2 with an estimated response time below 60 seconds.

Abstract The present work aimed to evaluate the effects of exogenous application of 24-epibrassinolide (24-EBL) in the physiological and biochemical responses of Solanum nigrum L exposed to nickel (Ni). After the seedling stage, 24-EBL treated and untreated plants were grown hydroponically for 28 days in the presence of 100 mu M NiSO4 center dot 6H(2)O. The exposure of S. nigrum to high levels of Ni resulted in a decrease of biometric parameters in both shoots and roots, with a partial recovery of both fresh weight and length in the 24-EBL pre-treated plants. Higher levels of Ni were found in roots, regardless of the pre-treatment with the brassinolide. Older leaves of Ni-exposed plants exhibited cell death symptoms, manifested in the form of chlorotic and necrotic spots. A decrease in photosynthetic pigments, soluble protein and relative RuBisCO contents were also observed in Ni-treated plants, however Ni-mediated toxicity was partially reverted by 24-EBL pre-treatment. Lipid peroxidation was chosen as a stress biomarker and malondialdehyde (MDA) levels did not change neither in roots nor in shoots. Soluble proline levels increased in response to Ni in both organs, but the pre-treatment with the phytohormone seems to mitigate the differences observed from the control shoots and roots. When ROS accumulation is concerned, generally Ni-exposed plants exhibited decreases in O-2(center dot)- and H2O2 levels regardless of being or not treated with 24-EBL. The Ni treatment led to a positive response of the plant's enzymatic antioxidant system. In shoots of Ni-stressed plants, an enhanced activity of superoxide dismutase (SOD) and ascorbate peroxidase (APX), accompanied by a decline of catalase (CAT) activity were observed. In roots, increases in SOD and CAT activities were detected in response to Ni, whilst APX was not. 24-EBL pre-treatment caused a decline in APX and CAT activities, while SOD activity was positively affected. Reverse transcriptase-PCR analysis revealed that mRNA transcript levels do not correlate with total enzymatic activity for SOD, CAT and APX, suggesting that these enzymes are regulated posttranscriptionally. Overall, the results suggested that Ni did not induce a severe oxidative stress in S. nigrum, yet the exogenous application of the brassinolide enhanced the plant tolerance to Ni.