In Silico Evaluation of Ibuprofen and Two Benzoylpropionic Acid Derivatives with Potential Anti-Inflammatory Activity

Inflammation is a complex reaction involving cellular and molecular components and an unspecific response to a specific aggression. The use of scientific and technological innovations as a research tool combining multidisciplinary knowledge in informatics, biotechnology, chemistry and biology are essential for optimizing time and reducing costs in the drug design. Thus, the integration of these in silico techniques makes it possible to search for new anti-inflammatory drugs with better pharmacokinetic and toxicological profiles compared to commercially used drugs. This in silico study evaluated the anti-inflammatory potential of two benzoylpropionic acid derivatives (MBPA and DHBPA) using molecular docking and their thermodynamic profiles by molecular dynamics, in addition to predicting oral bioavailability, bioactivity and toxicity. In accordance to our predictions the derivatives proposed here had the potential capacity for COX-2 inhibition in the human and mice enzyme, due to containing similar interactions with the control compound (ibuprofen). Ibuprofen showed toxic predictions of hepatotoxicity (in human, mouse and rat; toxicophoric group 2-arylacetic or 3-arylpropionic acid) and irritation of the gastrointestinal tract (in human, mouse and rat; toxicophoric group alpha-substituted propionic acid or ester) confirming the literature data, as well as the efficiency of the DEREK 10.0.2 program. Moreover, the proposed compounds are predicted to have a good oral bioavailability profile and low toxicity (LD50 < 700 mg/kg) and safety when compared to the commercial compound. Therefore, future studies are necessary to confirm the anti-inflammatory potential of these compounds

Bozepinib: A Promising Selective Derivative Targeting Breast Cancer Stem Cells

Bozepinib is a potent antitumour compound that shows an IC50 of 0.166 μM against MDA-MB-231 human breast cancer cell line. It is also a very selective drug that presents a therapeutic index (TI) of 11.0 against MDA-MB-231 in relation to the normal MCF-10A. It is important to identify new cancer stem-like cells (CSCs) anticancer drugs to struggle against the resistance and the high risk of relapse in patients. In the present chapter, we show how bozepinib demonstrated selectivity on cancer cells and showed an inhibitory effect over kinases involved in carcinogenesis, proliferation and angiogenesis. Bozepinib inhibits HER-2 signaling pathway and JNK and ERK kinases. In addition, it has an inhibitory effect on AKT and VEGF together with anti-angiogenic and anti-migratory activities. Interestingly, bozepinib suppresses the formation of both mammo- and colonospheres and eliminated ALDH+ CSC subpopulations at a low micromolar range similar to salinomycin. It also induces the downregulation of SOX2, c-MYC and β-CATENIN and upregulation of the GLI-3 Hedgehog signaling repressor. Finally, bozepinib shows in vivo antitumor and anti-metastatic efficacy in xenotransplanted nude mice without presenting subacute toxicity. However, further studies in cancer patients are needed to confirm the therapeutic potential of bozepinib

Symmetrical Pyridinium-Phanes and –Diazacyclophanes — Promising Heterocyclic Scaffolds for the Development of Anti-Leishmanial Agents

There is an urgent need for better drugs for a more successful fight against leishmaniasis, one of the most important neglected diseases caused by the parasite Leishmania. We have recently synthesized several symmetrical pyridinium compounds belonging to two different series: bis-pyridinium and bis-quinolinium acyclic structures and bis-pyridinium diazacyclophanes derivatives. The first series of bis-pyridinium derivatives have been found to display activity against promastigotes and intracellular amastigotes of Leishmania donovani and Leishmania major, with EC50 values lower than 1 μM. The majority of compounds show a similar behavior in both Leishmania species, being slightly more active against intracellular amastigotes of L. major. The series of bis-pyridinium diazacyclophanes can be considered as rigid analogues of the previous bis-cationic ones. The activity of these compounds has also been evaluated against promastigotes and intracellular amastigotes of L. donovani and L. major. All the diazacyclophanes are more active against L. major, with EC50 values of between 1 and 17 μM in intracellular amastigotes, and in some cases they present a higher selectivity index than the reference anti-leishmanial drugs such as amphotericin B and miltefosine. In conclusion, these bis-quaternary compounds represent promising candidates as potential therapeutic agents against leishmaniasis

Development of Biotransamination Reactions towards the 3,4-Dihydro-2H-1,5-benzoxathiepin-3- amine Enantiomers

The stereoselective synthesis of chiral amines is an appealing task nowadays. In this context, biocatalysis plays a crucial role due to the straightforward conversion of prochiral and racemic ketones into enantiopure amines by means of a series of enzyme classes such as amine dehydrogenases, imine reductases, reductive aminases and amine transaminases. In particular, the stereoselective synthesis of 1,5-benzoxathiepin-3-amines have attracted particular attention since they possess remarkable biological profiles; however, their access through biocatalytic methods is unexplored. Amine transaminases are applied herein in the biotransamination of 3,4-dihydro-2H-1,5-benzoxathiepin-3-one, finding suitable enzymes for accessing both target amine enantiomers in high conversion and enantiomeric excess values. Biotransamination experiments have been analysed, trying to optimise the reaction conditions in terms of enzyme loading, temperature and reaction times.Financial support has been received from the Spanish Ministry of Economy and Competitiveness (MINECO, Projects CTQ2013-40855-R and CTQ2016-75752-R), Junta de Andalucía (Project CS2016.1) and Gobierno de Aragon-FEDER (Research group E19_17R)

Spanish facilities and fisrst results in measuring thermodynamic temperature using the radiance method

Newport Pagnell, Buckinghamshire, May 18-19 2015; https://royalsociety.org/science-events-and-lectures/2015/05/new-kelvin/Currently, the dissemination of the kelvin, according to the International Temperature Scale (ITS-90), at high temperatures is realised at the Centro Español de Metrología (CEM) by using the fixed points of Ag and Cu and a standard radiation thermometer. Recently, absolute radiometry has been proposed by the CCT Working Group 5 [1] to be included in future revisions of the Mise-en-Practique for the kelvin (MeP-K). The Centro Español de Metrologia (CEM) in collaboration with the Instituto de Óptica of the Consejo Superior de Investigaciones Científicas (IO-CSIC) has been working in the following lines linked to this new alternative to disseminate the kelvin: ¿ Absolute calibration, i.e., calibration in terms of the thermodynamic temperature, of commercial radiation thermometers, by using a facility based on a monochromator and a high stability lamp [2]. At present, the uncertainties of these measurements, obtained with a KE-LP2 radiation thermometer, are about the ones obtained with the ITS-90 method, i. e. from 0,3 K to 1,1 K (from 1084,62 °C to 2474 °C, k = 2). Some improvements in the facilities described in [2] have been implemented in order to reduce uncertainty. ¿ Development of a filter radiometer to measure the thermodynamic temperature. It has been designed by CEM based in NPL previous work [3]. This filter radiometer can be calibrated with a laser based experimental setup, which improves the above measurement uncertainty [4]: from 0,2 K to 0,7 K (from 1084,62 °C to 2474 °C, k = 2). Because of some problems with the radiometer stability at 2500 °C, some changes in the design have been done. The facilities used in [2] and [4] are currently been developed at CEM site as the transportation of the instruments for calibration has caused significant drifts. A complete description of IO-CSIC and new CEM facilities will be presented, together with the results obtained on the determination of the WP1 InK cells thermodynamic temperatures by using both, a radiation thermometer with an absolute calibration, and a filter radiometer.Peer Reviewe

Influencia del tamaño de pigmento en la distancia de detección del sparkle

XI Reunión Nacional de Óptica Día de la Luz; Facultad de Ciencias • Universidad de Salamanca 1 - 4 Septiembre, 2015; http://rno11.usal.es/programaSe diseñó un experimento psicofísico para evaluar la influencia del tamaño del pigmento de efecto en la distancia de detección del sparkle. Los resultados mostraron que a mayor tamaño de pigmento, mayor distancia de detección. Además, la correlación visual e instrumental (distancia de detección vs. grado de sparkle (SG)) sigue una relación lineal, sin embargo, no existe una relación lineal con el tamaño de pigmento: la distancia es máxima para un tamaño inferior al tamaño máximo.Peer Reviewe

Color characterization of coatings with diffraction pigments

Coatings with diffraction pigments present high iridescence, which needs to be characterized in order to describe their appearance. The spectral bidirectional reflectance distribution functions (BRDFs) of six coatings with SpectraFlair diffraction pigments were measured using the robot-arm-based goniospectrophotometer GEFE, designed and developed at CSIC. Principal component analysis has been applied to study the coatings of BRDF data. From data evaluation and based on theoretical considerations, we propose a relevant geometric factor to study the spectral reflectance and color gamut variation of coatings with diffraction pigments. At fixed values of this geometric factor, the spectral BRDF component due to diffraction is almost constant. Commercially available portable goniospectrophotometers, extensively used in several industries (automotive and others), should be provided with more aspecular measurement angles to characterize the complex reflectance of goniochromatic coatings based on diffraction pigments, but they would not require either more than one irradiation angle or additional out-of-plane geometries.European Metrology Research Programme (EMRP) (EMRP IND52); Comunidad de Madrid (SINFOTON-CM: S2013/MIT-2790); Ministerio de Economía y Competitividad (MINECO) (DIP2015-65814)

Visibility of sparkle in metallic paints

For suitable illumination and observation conditions, sparkles may be observed in metallic coatings. The visibility of these sparkles depends critically on their intensity, and on the paint medium surrounding the metallic flakes. Based on previous perception studies from other disciplines, we derive equations for the threshold for sparkles to be visible. The resulting equations show how the visibility of sparkles varies with the luminosity and distance of the light source, the diameter of the metallic flakes, and the reflection properties of the paint medium. The predictions are confirmed by common observations on metallic sparkle. For example, under appropriate conditions even metallic flakes as small as 1 μm diameter may be visible as sparkle, whereas under intense spot light the finer grades of metallic coatings do not show sparkle. We show that in direct sunlight, dark coarse metallic coatings show sparkles that are brighter than the brightest stars and planets in the night sky. Finally, we give equations to predict the number of visually distinguishable flake intensities, depending on local conditions. These equations are confirmed by previous results. Several practical examples for applying the equations derived in this article are provided.European Metrology Research Programme (EMRP) Spanish Ministry of Economy and Competitiveness(DPI2011-30090-C02) Comunidad de Madrid (CM: S2013/MIT-2790). The EMRP is jointly funded by the EMRP participating countries within the European Association of National Meteorlogy (EURAMET) and the European Union