We describe a general and practical strategy for the direct one-step incorporation of a tunable solubility module at the boron atom of F-BODIPY dyes. The tethering reaction uses easy-to-handle reagents, has broad functional group compatibility and proceeds under mild conditions without requiring any pre-functionalization of the starting F-BODIPY to yield the solubility-tagged O-BODIPY derivative in 51–86\% yield. The module can be introduced at the end of the synthetic route without perturbing the fluorophore scaffold, thus minimizing difficulties in product isolation. Its orthogonal geometrical arrangement with respect to the plane of the BODIPY chromophore hampers intermolecular aggregation processes that quench fluorescence, while the covalent attachment to the boron atom has a minimal effect on the absorption properties. Fully water-soluble and hydrolytically stable BODIPYs were prepared by incorporating either neutral (tetra- and octaethylene glycol chains) or zwitterionic (sulfobetaine) hydrophilic tags in the module. The new dyes are valuable live cell imaging probes that ameliorate the undesired partitioning into lipophilic compartments that is often observed for standard BODIPYs. This strategy can be readily adapted to the general and highly practical post-synthetic introduction of new functionalities into F-BODIPY dyes, including phase-tagging, by appropriately choosing the nature of the chemical tags attached to the module. © 2019 Elsevier Ltd

Oligosaccharides are gaining importance because of their beneficial properties in human health. They normally appear in natural and synthetic products as complex mixtures of different monomeric units, glycosidic linkages and degrees of polymerization, being disaccharides and trisaccharides usually the most abundant ones. Although liquid chromatography-mass spectrometry is a useful technique for oligosaccharides analysis, the similarity of their structures makes difficult their characterization. Moreover, there is still scarce information about the relationship between carbohydrate chemical structure, mass spectra and chromatographic data. Then, in this work, chromatographic parameters for 23 disaccharides with different linkages and monomeric units (glucose, galactose, mannose and fructose) were determined using porous graphitized and hydrophilic interaction liquid chromatography columns. Moreover, diagnostic ions of these disaccharides obtained by tandem mass spectra (MS2) were established by stepwise linear discriminant analysis. The relationship between carbohydrate chemical structure and their chromatographic retention data and characteristic ions obtained by multiple-stage mass spectrometry (MSn) was successful in establishing some specific criteria that allowed the characterization of trisaccharides with different structural features. © 2019

Byproducts from artichoke represent the majority of the mass collected from the plant and constitute an interesting source of bioactive compounds such as inositols and caffeoylquinic acids. In this work, a microwave assisted extraction (MAE) methodology was developed for the simultaneous extraction of these compounds from artichoke stalks, leaves, receptacles and external bracts. Optimal MAE conditions to maximize the extraction of these bioactives and the antioxidant activity were 97 °C, 3 min, ethanol:water (50:50, v/v). Moreover, a GC–MS methodology was also developed for the simultaneous determination of these compounds in a single run; optimal derivatization conditions were achieved using hexamethyldisilazane and N,O-bis(trimethylsilyl)trifluoroacetamide with 1\% trimethylchlorosilane. Artichoke receptacle extracts were the richest in caffeoylquinic acids (28–35 mg g−1 dry sample), followed by the bracts (9–18 mg g−1 dry sample), while those from leaves showed the highest concentrations of inositols (up to 15 mg g−1 dry sample). Receptacle extracts also had the highest antioxidant activity (123 mg TE g−1 dry sample) and the greatest concentration of total phenolic compounds (47 mg GAE g−1 dry sample). Therefore, the developed methodology could be considered as a valuable procedure to obtain and characterize bioactive ingredients with industrial interest from artichoke byproducts, opening new routes of revalorization of artichoke agro-industrial residues. © 2019

The unexpected stereospecific synthesis of (±)-cis-1-aryl-3-oxo-2,3-dihydro-1H-benzo[f]chromene-2-carbonitriles (2) and (±)-trans-4-aryl-2-oxo-3,4-dihydro-2H-benzo[h]chromene-3-carbonitriles (4) from (±)-3-amino-1-aryl-1H-benzo[f]chromene-2-carbonitriles (1) and (±)-2-amino-4-aryl-4H-benzo[h]chromene-3-carbonitriles (3), respectively, by reacting them in formic acid (88\%), at reflux, is reported. A DFT analysis has been applied with success to justify these highly stereospecific reactions. © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Selenoesters and the selenium isostere of phthalic anhydride are bioactive selenium compounds with a reported promising activity in cancer, both due to their cytotoxicity and capacity to reverse multidrug resistance. Herein we evaluate the antiviral, the biofilm inhibitory, the antibacterial and the antifungal activities of these compounds. The selenoanhydride and 7 out of the 10 selenoesters were especially potent antiviral agents in Vero cells infected with herpes simplex virus-2 (HSV-2). In addition, the tested selenium derivatives showed interesting antibiofilm activity against Staphylococcus aureus and Salmonella enterica serovar Typhimurium, as well as a moderate antifungal activity in resistant strains of Candida spp. They were inactive against anaerobes, which may indicate that the mechanism of action of these derivatives depends on the presence of oxygen. The capacity to inhibit the bacterial biofilm can be of particular interest in the treatment of nosocomial infections and in the coating of surfaces of prostheses. Finally, the potent antiviral activity observed converts these selenium derivatives into promising antiviral agents with potential medical applications. © 2019 by the authors.

Based on the monoamine oxidase (MAO) inhibition properties of aminoheterocycles with a carbonitrile group we have carried out a systematic exploration to discover new classes of carbonitriles endowed with dual MAO and AChE inhibitory activities, and Aβ anti-aggregating properties. Eighty-three nitrile-containing compounds, 13 of which are new, were synthesized and evaluated. in vitro screening revealed that 31, a new compound, presented the best lead for trifunctional inhibition against MAO A (0.34 μM), MAO B (0.26 μM), and AChE (52 μM), while 32 exhibited a lead for selective MAO A (0.12 μM) inhibition coupled to AChE (48 μM) inhibition. Computational analysis revealed that the malononitrile group can find an advantageous position with the aromatic cleft and FAD of MAO A or MAO B. However, the total binding energy can be handicapped by an internal penalty caused by twisting of the ligand molecule and subsequent disruption of the conjugation (32 in MAO B compared to the conjugated 31). Conjugation is also important for AChE as well as the hydrophilic character of malononitrile that allows this group to be in close contact with the aqueous environment as seen for 83. Although the effect of 31 and 32 against Aβ1–42, was very weak, the effect of 63 and 65, and of the new compound 75, indicated that these compounds were able to disaggregate Aβ1–42 fibrils. The most effective was 63, a (phenylhydrazinylidene)propanedinitrile derivative that also inhibited MAO A (1.65 μM), making it a potential lead for Alzheimer's disease application. © 2019 Wiley Periodicals, Inc.

Tacrine was the first drug to be approved for Alzheimer’s disease (AD) treatment, acting as a cholinesterase inhibitor. The neuropathological hallmarks of AD are amyloid-rich senile plaques, neurofibrillary tangles, and neuronal degeneration. The portfolio of currently approved drugs for AD includes acetylcholinesterase inhibitors (AChEIs) and N-methyl-d-aspartate (NMDA) receptor antagonist. Squaric acid is a versatile structural scaffold capable to be easily transformed into amide-bearing compounds that feature both hydrogen bond donor and acceptor groups with the possibility to create multiple interactions with complementary sites. Considering the relatively simple synthesis approach and other interesting properties (rigidity, aromatic character, H-bond formation) of squaramide motif, we combined this scaffold with different tacrine-based derivatives. In this study, we developed 21 novel dimers amalgamating squaric acid with either tacrine, 6-chlorotacrine or 7-methoxytacrine representing various AChEIs. All new derivatives were evaluated for their anti-cholinesterase activities, cytotoxicity using HepG2 cell line and screened to predict their ability to cross the blood-brain barrier. In this contribution, we also report in silico studies of the most potent AChE and BChE inhibitors in the active site of these enzymes. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.

In this study, the hydrothermal upgrading (HTU) of high sulfur-content heavy oil was investigated at sub-critical (Sub-CW), near-critical (NCW) and supercritical water (SCW) conditions. Products obtained after HTU, including gases, liquid, and coke (if formed), were analyzed to understand the upgrading performance at different conditions. At Sub-CW (200, 250, and 300 °C), 250 °C is the optimum temperature where a viscosity reduction from 2073 to 1758 mPa s was achieved with a slight removal of sulfur (mainly sulfur) and the generation of a small amount of light and non-condensable hydrocarbons in gas phase (C1–C4, isoalkanes and alkenes, H2S, CO2 and H2, etc.). At NCW (350 °C) and SCW (400 °C), heavy oil was upgraded into light oil with a significant removal of heteroatoms, an increase of saturates content, a reduction of aromatics, resins and asphaltenes contents, and a high yield of light gaseous hydrocarbons (mainly methane). Simultaneously, each SARA fraction was also greatly ameliorated: the content of light alkanes with low molecular weight in saturates was increased, diaromatics content in aromatics was increased with a reduction of polyaromatics content, aromatics-type carbon atoms in resins was increased with a decrease in aliphatic hydrocarbons. Moreover, MALDI-TOF measurements of asphaltenes show that the molecular weights of asphaltenes were reduced. All these results indicated that HTU at Sub-CW can be used for heavy oil pre-treatment (in-situ or ex-situ upgrading) considering its main effect of viscosity reduction with a small removal of heteroatoms, while HTU at NCW and SWC has a great potential in in-situ and ex-situ upgrading and oil refining as it can convert heavy oil into light oil. © 2019 Elsevier B.V.

The ubiquitous occurrence of perfluoroalkyl substances (PFAS) in the open ocean has been previously documented, but their vertical transport and oceanic sinks have not been comprehensively characterized and quantified at the oceanic scale. During the Malaspina 2010 circumnavigation expedition, 21 PFAS were measured at the surface and at the deep chlorophyll maximum (DCM) in the Atlantic, Indian and Pacific oceans. In this work, we report an extended data set of PFAS dissolved phase concentrations at the DCM. ∑PFAS at the DCM varied from 130 to 11000 pg L-1, with a global average value of 500 pg L-1. Perfluorooctanesulfonate (PFOS) abundance contributed 39\% of ∑PFAS, followed by perfluorodecanoate (PFDA, 17\%), and perfluorohexanoate (PFHxA, 12\%). The relative contribution of the remaining compounds was below 10\%, with perfluorooctanoate (PFOA) contributing only 5\% to PFAS measured at the DCM. Estimates of vertical diffusivity, derived from microstructure turbulence observations in the upper (<300 m) water column, allowed the derivation of PFAS eddy diffusive fluxes from concurrent field measurements of eddy diffusivity and PFAS concentrations. The PFAS concentrations at the DCM predicted from an eddy diffusivity model were lower than field-measured concentrations, suggesting a relevant role of other vertical transport mechanisms. Settling fluxes of organic matter bound PFAS (biological pump), oceanic circulation and potential, yet un-reported, biological transformations are discussed. © 2019 The Royal Society of Chemistry.

BACKGROUND: Many factors are involved in Alzheimer's Disease (AD) such as amyloid plaques, neurofibrillary tangles, cholinergic deficit and oxidative stress. To counter the complexity of the disease the new approach for drug development is to create a single molecule able to act simultaneously on different targets. OBJECTIVE: We conceived eight drug likeliness compounds targeting the inhibition of cholinesterases and the scavenging of radicals. METHODS: We synthesised the new molecules by the Passerini multicomponent reaction and evaluated their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) as well as their antioxidant activities by the Oxygen Radical Absorbance Capacity (ORAC) assay. The lipinski's rule for drug likeness and in silico ADME prediction was also performed. RESULTS: Compounds 4f [IC50 (EeAChE) = 0.30 μM; IC50 (eqBuChE) = 0.09 μM; ORAC = 0.64 TE] and 4h [IC50 (EeAChE) = 1 μM; IC50 (eqBuChE) = 0.03 μM; ORAC = 0.50 TE] were identified as hits for further development. CONCLUSION: The Passerini reaction allowed us the facile synthesis of ditarget molecules of interest for the treatment of AD. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.

Chondroitin sulfates are linear anionic sulfated polysaccharides found in biological tissues, mainly within the extracellular matrix, which are degraded and altered by specific lyases depending on specific time points. These polysaccharides have recently acquired relevance in the pharmaceutical industry due to their interesting therapeutic applications. As a consequence, chondroitin sulfate (CS) lyases have been widely investigated as tools for the development of new pharmaceuticals based on these polysaccharides. This review focuses on the major breakthrough represented by chondroitin sulfate-degrading enzymes and their structures and mechanisms of function in addition to their major applications. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.

The last decade has witnessed a renewed interest in selenium (Se) as an element able to prevent a range of illnesses in humans, mainly through supplementation. However, such supplementation relies on species such as sodium selenite or selenomethionine, which proved to have limited solubility and bioavailability, thus leading to limited activity. To overcome this limitation, other selenium species need to be explored, such as phthalic selenoanhydride (R-Se), which is soluble in physiological media. R-Se releases various reactive selenium species (RSeS), including hydrogen selenide (H2Se), that can interact with cellular components, such as glutathione (GSH) and hydrogen sulfide (H2S). This interplay between R-Se and the cellular components provides a sophisticated biochemical release mechanism that could be behind the noteworthy biological activities observed for this compound. In order to investigate the interactions of phthalic chalcogen anhydrides with H2S or GSH, we have employed UV-vis spectrophotometry, electron paramagnetic resonance spectroscopy (EPR) and plasmid DNA (pDNA) cleavage assay. We found that apart from R-Se, the other analogues do not have the ability to scavenge the cPTIO radical or to cleave pDNA on their own. In contrast, the scavenging potency for the cPTIO radical and for the O2- radical exerted by R-Se and its sulfur analogue (R-S) significantly increased when they were evaluated in the presence of H2S. However, GSH only changed the radical scavenging activity of R-Se. These new discoveries may explain some of the biological activities associated with this class of compounds and open a new approach to ascertain the possible mechanisms underlying their biological actions. © 2019 The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.

Bird migration studies have been given added impetus recently thanks to the miniaturisation of tracking devices. However, tracking methodologies have remained impractical for the smallest pelagic species and so important gaps in knowledge still exist. In the case of the European Storm-petrel Hydrobates pelagicus, while Atlantic populations are thought to overwinter along the south-western African coast, the winter quarters of Mediterranean birds remain more enigmatic. We performed stable isotope analysis (SIA) of C and N on P1, S8 and P10 feathers from 33 adult birds captured in three Atlantic colonies and 156 adult birds in seven western Mediterranean colonies to infer their wintering areas. In addition, we collated all observational field data, both from peer-reviewed publications and the wider literature, to complement our inferences from SIA. Within the Atlantic, isotopic profiles of feathers moulted at the breeding grounds (P1) differed between birds captured at northern Atlantic and Canary Islands colonies, but were similar for feathers moulted in winter quarters (S8 and P10), indicating low migratory connectivity. Isotopic values of feathers from western Mediterranean birds differed from those of Atlantic birds and showed Mediterranean values for all feathers, indicating that the former overwinter in Mediterranean waters. Variance in the isotopic values was greater in winter than in breeding season feathers, suggesting that birds disperse over larger areas in winter. Isotopic values of feathers moulted during the non-breeding period could match a post-breeding movement towards the southern and eastern Mediterranean. This inference matches the distribution of the few winter reports, which are mainly concentrated in the south-central Mediterranean, mostly in the Tunisian Platform. Our results suggest that this region is the principal wintering area of Mediterranean Storm-petrels.-Martínez, C., Roscales, J.L., Sanz-Aguilar, A. & González-Solís, J. (2019). Inferring the wintering distribution of the Mediterranean populations of European Storm-petrels Hydrobates pelagicus melitensis from stable isotope analysis and observational field data. © 2019 SEO/ Birdlife. All rights reserved.

Tunable chemoselectivity (O- versus C-attack) in the rhodium-catalyzed reactions of allenols with 4-substituted-1-sulfonyl-1,2,3-triazoles has been achieved through the replacement of the 4-aryl substituent by a 4-acetyl moiety. (Figure presented.). © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

This work is focused on mechanistic studies of the transfer of an adenylyl group (Adenoside-5'-monophosfate) from adenosine 5'-triphosphate (ATP) to a OH-4' hydroxyl group of an antibiotic. Using hybrid quantum mechanics/molecular mechanics (QM/MM) techniques, we study the substrate and base-assisted mechanisms of the inactivation process of kanamycin A (KAN) catalyzed by 4'-O-Nucleotidyltransferase [ANT(4')], an active enzyme against almost all aminoglycoside antibiotics. Free energy surfaces, obtained with Free Energy Perturbation methods at the M06-2X/MM level of theory, show that the most favorable reaction path presents a barrier of 12.2 kcal·mol-1 that corresponds to the concerted activation of O4' from KAN by Glu145. In addition, the primary and secondary 18O kinetic isotope effects (KIEs) have been computed for bridge O3α, and non-bridge O1α, O2α, and O5' atoms of ATP. The observed normal 1°-KIE of 1.2\% and 2°-KIE of 0.07\% for the Glu145-assisted mechanism are in very good agreement with experimentally measured data. Additionally, based on the obtained results, the role of electrostatic and compression effects in enzymatic catalysis is discussed. © 2019 Martí, Bastida and Świderek.

In the last few years, biopharmaceuticals—therapeutic drugs which are generally obtained by using molecular biology techniques—have become a major growing sector in pharmaceutical industry. A large part of these biopharmaceuticals are therapeutic glycoproteins. The production of these drugs and their purification process are implying the development of efficient analytical methods, which allow quick and reliable control of the manufacturing process and ensuring the regulatory compliance about the quality of these drugs. Capillary gel electrophoresis (CGE) in the presence of sodium dodecyl sulfate (SDS) is becoming a method of choice in the quality control of these biopharmaceuticals. On the other hand, CGE can be improved if analyses are carried out in microchip format. This chapter reports a detailed microchips gel electrophoresis (MGE) method to separate glycosylated and deglycosylated forms of α1-acid glycoprotein (AGP) labeled with Chromeo P540, using SU-8 microchips and laser induced fluorescence detection. Due to the analogy between AGP and some therapeutic glycoproteins, we have selected AGP as a model system to illustrate the potential of MGE in the analysis of this type of biopharmaceutical compounds. © Springer Science+Business Media, LLC, part of Springer Nature 2019.

The Capillary Electrophoresis (CE) profile of isoforms (peaks) of a glycoprotein can be useful to show alterations in its posttranslational modifications (PTMs) linked to diseases. These changes can modify the electrophoretic mobility of these isoforms in a minor extent and, therefore, very reproducible CE methods are needed to detect them. In this chapter, a method for the analysis of prostate-specific antigen (PSA) by Capillary Zone Electrophoresis (CZE) with UV detection is detailed. High reproducibility in the separation of a large number of PSA isoforms is achieved by performing capillary conditioning in acid media and by using a background electrolyte (BGE) at pH 8.0 formulated with decamethonium bromide and urea. © Springer Science+Business Media, LLC, part of Springer Nature 2019.

Malignant diseases present a serious public health burden and their treatment with traditional chemotherapy cannot be considered an all-round solution, due to toxic side effects. Selenium compounds (Se-compounds) have received substantial attention in medicinal chemistry, especially in experimental chemotherapy, both as cytotoxic agents and adjuvants in chemotherapy. A checkerboard microplate method was applied to study the drug interactions of Se-compounds and clinically relevant chemotherapeutic drugs against the multidrug-resistant (MDR) subtype of mouse T-lymphoma cells overexpressing the ABCB1 transporter. Se-compounds showed synergistic interactions with chemotherapeutic agents targeting the topoisomerase enzymes or the microtubule apparatus. The ketone-containing selenoesters showed synergism at lower concentrations (1.25 µM). Most of the tested compounds interacted antagonistically with alkylating agents and verapamil. A thiophene-containing Se-compound showed synergism with all tested drugs, except cisplatin. While the exact mechanism of drug interactions is yet unknown, the potency of the selenocompounds as efflux pump inhibitors or the potentiation of their efficacy as reactive oxygen species modulators may play a role in their complementary activity against the tested MDR lymphoma cell line. © 2019 by the authors.

A porous polymer containing a fluorophenylphenanthroimidazole core was easily prepared via one-pot Suzuki-Miyaura cross-coupling reactions under microwave heating. These new metal-free polymers have demonstrated heterogeneous photocatalytic activity toward aza-Henry reaction with reasonable recyclability. Their preparation require a minimal workup to build porous networks with control over the apparent surface area and pore volume from suitable molecular building blocks containing 2-(1H-phenanthro[9,10-d]imidazol-2-yl)-3,5-difluorophenol (PhIm-2F), as rigid and multitopic node, which afforded a conjugated porous polymer (CPP-PhIm-2F). A series of fluorinated ligands have shown their capability in the preparation of soluble and supported cationic Ru(bpy) 2 (F-phenanthroimidazole) complexes by reaction with Ru(bpy) 2 Cl 2 and demonstrating a beneficial effect of two fluorine atoms on the photocatalytic effect. © 2018 American Chemical Society.

Atmospheric deposition of semivolatile aromatic hydrocarbons accounts for an important input of organic matter to the surface ocean. Nevertheless, the biogeochemical cycling and sinks of semivolatile aromatic hydrocarbons in the ocean remain largely uncharacterized. Here we present measurements of 64 polycyclic aromatic hydrocarbons in plankton and seawater from the Atlantic, Pacific, Indian and Southern Oceans, as well an assessment of their microbial degradation genes. Concentrations of the more hydrophobic compounds decreased when the plankton biomass was higher, consistent with the relevance of the biological pump. The mass balance for the global oceans showed that the settling fluxes of aromatic hydrocarbons in the water column were two orders of magnitude lower than the atmospheric deposition fluxes. This imbalance was high for low molecular weight hydrocarbons, such as phenanthrene and methylphenanthrenes, highly abundant in the dissolved phase. Parent polycyclic aromatic hydrocarbons were depleted to a higher degree than alkylated polycyclic aromatic hydrocarbons, and the degradation genes for polycyclic aromatic hydrocarbons were found to be ubiquitous in oceanic metagenomes. These observations point to a key role of biodegradation in depleting the bioavailable dissolved hydrocarbons and to the microbial degradation of atmospheric inputs of organic matter as a relevant process for the marine carbon cycle. © 2019, The Author(s), under exclusive licence to Springer Nature Limited.