Visible light-promoted and gold-photoredox-catalyzed reactions of heteroatom (N, S, Se, O) tethered alkynes with arenediazonium salts selectively proceeded to build vicinal diaryl-substituted 2H-benzo[e][1,2]thiazine 1,1-dioxides (benzosultams), benzoselenophenes, benzothiophenes, 4H-chromen-4-ones (flavones), 3H-indoles, 1H-isochromen-1-ones (isocoumarins), and 4H-thiochromen-4-ones (thioflavones). Moreover, the utility of functionalized 3H-indoles as precursors for further elaboration has been demonstrated with the switchable and facile preparation of 1H-indoles, 2-oxindoles, and 3-oxindolines. (Figure presented.). © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Light harvesting is a natural phenomenon that scientists try to mimic in artificial systems. Having this in mind, attention has been focused on using new smart-materials for photonics. Herein, we report on the photobehaviour of a Zr-NDC MOF (NDC = dimethyl 2,6-naphthalenedicarboxylate) and its composite material, Coumarin153@Zr-NDC, embedded within a polymeric membrane of poly[bisphenol A carbonate-co-4,4′-(3,3,5-trimethylcyclohexylidene)diphenol carbonate] (PC). For the mixed matrix membrane (MMM) Zr-NDC/PC, we observed interparticle excimer-like formation, taking place in times shorter than 15 ps and giving rise to a red-shifted broad emission band. The interparticle interactions are supported by the SEM images, as they reflect the contact between the MOF crystals. The C153@Zr-NDC/PC material presents an energy transfer (ET) process from the excited MOF to the trapped C153 molecules in 820 ps, with a 35 nm red-shifted emission band corresponding to C153 in PC. The fluorescence quantum yield, as a result of this ET from the MOF, is high enough (25\%) to explore the possibility of using this new composite material in a LED device. To elucidate the observed photobehavior, we compared it with those of C153/PC and (2,6-NDC + C153)/PC films. These results shed light on the spectroscopic and dynamical properties of these new composite materials formed by a highly fluorescent molecule, and easily synthesized MOFs and polymeric matrices, opening the way for more research based on these mixed inorganic and organic compounds for possible applications in the fields of luminescence sensing and emitting devices. © the Owner Societies 2017.

Herein we report an efficient two step synthesis and biological assessment of 12 racemic tetrahydropyranodiquinolin-8-amines derivatives as antioxidant, cholinesterase inhibitors and non-hepatotoxic agents. Based on the results of the primary screening, we identified 7-(3-methoxyphenyl)-9,10,11,12-tetrahydro-7H-pyrano[2,3-b:5,6-h']diquinolin-8-amine (2h) as a particularly interesting non-hepatotoxic compound that shows moderate antioxidant activity (1.83 equiv Trolox in the ORAC assay), a non competitive inhibition of hAChE (IC50= 0.75 ± 0.01 μM), and brain permeable as determined by the PAMPA-Blood Brain Barrier assay. © 2016 Elsevier Masson SAS

Tacrine was the first drug to display beneficial effects on cognitive impairment of Alzheimer Disease (AD) patients. Unfortunately, many treated patients displayed related hepatotoxicity, and hence this drug was withdrawn. Notwithstanding, recent efforts have been directed to design small tacrine analogues targeting the underlying pathogenic mechanisms of AD. In this context, we have developed a number of pyranotacrines by changing the benzene fused ring in tacrine by a 4H-pyran. Based on this strategy, in this account we will show the tacrine analogues that we have designed, synthesized and evaluated as potential multipotent agents for AD in the last years. We have demonstrated that this approach is possible, and that a number of readily available tacrine analogues show cholinesterase inhibition power, as well as other pharmacological properties, such as calcium channel blockade, antioxidant properties, neuroprotection, Aβ-amyloid inhibition aggregation capacity, etc., making them suitable multipotent molecules for further development for the potential treatment of AD. © 2017 Bentham Science Publishers.

Tacrine was the first drug approved by FDA (US) for the treatment of Alzheimer’s disease suffering patients. Nowadays, this agent has been withdrawn from the clinics due to secondary effects, which, most importantly, include hepatotoxicity. However, the research on new tacrine analogues devoid of these therapeutically undesirable effects, but benefiting of their high and well known positive cholinergic power, has produced a number of new non-hepatotoxic tacrines. In this context, our laboratory has recently prepared a new set of heterocyclic tacrines by changing the benzene ring present in tacrine by appropriate heterocyclic motifs. Based on this approach, in this review we summarize the results that we have found in the ChromenoPyranoTacrines, one of the families of tacrine analogues. This highlights their pharmacological profile, such as their cholinesterase inhibition power, calcium channel blockade, antioxidant capacity, Aβ-anti-aggregating, and neuroprotective properties. As a result of this work we have identified permeable, neuroprotective MTD tacrines racemic hit-tacrines 11-amino-12-(3,4,5-trimethoxyphenyl)-7,9,10,12-tetrahydro-8H-chromeno[2,3-b]quinolin-3-ol (6g) and 14-(3,4-dimethoxyphenyl)-9,11,12,14-tetrahydro-10H-benzo[5,6] chromeno [2,3-b] quinolin-13-amine (7i),devoid of toxic effects and showing potent anti-cholinesterasic properties, that deserve attention and further development in order to find new, and more efficient drugs, for AD therapy. © 2017 Bentham Science Publishers.

In the present paper, we describe the synthesis of novel monomers prepared by regioselective Michael addition to asymmetric divinylic compounds. This chemoselectivity was experimentally studied employing different reaction conditions and theoretically calculated using chemical global and local descriptors. The global reactivity data show that incoming nucleophilic secondary amines preferentially attack the acrylic derived units acrylate and acrylamide, while deactivated methacrylate and N-vinyl-pyrrolidone require harder reaction conditions, which leads to the formation of by-products. Moreover, it is demonstrated that the presence of two vinyl units within a studied divinylic agent leads to a significant increase in its global reactivity parameters. Besides, the local reactivity parameters of asymmetric divinyl compounds show a preference for an attack at the Cβ of activated units compared to the Cβ center of deactivated units. Based on these results, asymmetric divinyl compounds are very interesting starting materials for the preparation of new functionalized monomers. © 2017 The Royal Society of Chemistry.

In this study, a chicken meat containing AgNPs (candidate reference material Nanolyse 14) has been used as a model matrix to study the fate and behaviour of AgNPs upon oral ingestion following an in vitro model that included saliva, gastric and intestinal digestions. The behaviour of a 40 nm AgNPs standard solution during the three digestion steps was also evaluated. Sample preparation conditions were optimised to prevent AgNPs oxidation and/or aggregation and to ensure the representativeness of the reported results. Total silver released from the test sample and the evaluated AgNP standard was determined by inductively coupled plasma mass spectrometry (ICPMS). The presence of both AgNPs and dissolved silver in the extracts was confirmed by single particle (SP)-ICPMS analysis. AgNPs were sized and the particle number concentration determined in the three digestion juices. Experimental results demonstrated differentiated behaviours for AgNP from the standard solution and the meat sample highlighting the relevance of using physiological conditions for accurate risk assessment. In the most realistic scenario assayed (i.e., spiked chicken meat analysis), only 13\% of the AgNPs present in the reference material would reach the intestine wall. Meanwhile, other bioaccessible dissolved forms of silver would account for as much as 44\% of the silver initially spiked to the meat paste. © 2016 Elsevier Ltd

The β-lactam ring (2-azetidinone) is found in classical antibiotics such as penicillins and cephalosporins. In addition, this fragment is also detected in compounds with other pharmacological profile, such as antidiabetic, anticancer and cholesterol absorption inhibition among others. Besides, to its biological relevance, the β-lactam ring is a versatile building block for the synthesis of a huge amount of acyclic and cyclic structures by selective fragmentation or rearrangement of each single bond. This chapter is devoted to the synthesis of five-membered heterocycles by ring expansion of β-lactams. The contributions presented in this chapter have been selected from the developments achieved mainly in the last 20 years, in addition to some remarkable early reports. © Springer International Publishing AG 2017.

A simple and convenient one-pot method has been used for the synthesis of new polycyclic compounds articulated around 3-cyanopyridine derivatives from 2-chloroquinolin-3-carbaldehydes, acetophenone derivatives, active methylene compounds, and ammonium acetate as a source of ammonia in the presence of catalytic amounts of PPh3at room temperature. The salient features of the protocol used are mild reaction conditions, good yields, short reaction time, safety, and high atom economy. No column chromatographic was needed, and pure products were obtained by simple filtration and washing with Et2O. © 2016 Wiley Periodicals, Inc.

Tunneling nanotubes (TnTs) are thin channels that temporally connect nearby cells allowing the cell-to-cell trafficking of biomolecules and organelles. The presence or absence of TnTs in human neoplasms and the mechanisms of TnT assembly remains largely unexplored. In this study, we have identified TnTs in tumor cells derived from squamous cell carcinomas (SCC) cultured under bi-dimensional and tri-dimensional conditions and also in human SCC tissues. Our study demonstrates that TnTs are not specific of epithelial or mesenchymal phenotypes and allow the trafficking of endosomal/ lysosomal vesicles, mitochondria, and autophagosomes between both types of cells. We have identified focal adhesion kinase (FAK) as a key molecule required for TnT assembly via a mechanism involving the MMP-2 metalloprotease. We have also found that the FAK inhibitor PF-562271, which is currently in clinical development for cancer treatment, impairs TnT formation. Finally, FAK-deficient cells transfer lysosomes/autophagosomes to FAK-proficient cells via TnTs which may represent a novel mechanism to adapt to the stress elicited by impaired FAK signaling. Collectively, our results strongly suggest a link between FAK, MMP-2, and TnT, and unveil new vulnerabilities that can be exploited to efficiently eradicate cancer cells.

A straightforward and atom-economical enantioselective approach to highly substituted tetrahydropyrans is reported. The process, which consists of an intermolecular gold-catalyzed [2+2+2] cycloaddition between allenamides, alkenes, and aldehydes, is efficiently catalyzed by both phosphoramidite- and chiral N-heterocyclic carbene-gold catalysts, occurs with complete chemoselectivity and regioselectivity, moderate diastereoselectivity, and moderate to very good enantioselectivities. © 2017 American Chemical Society.

Stroke represents one of the most common causes of brain's vulnerability for many millions of people worldwide. The plethora of physiopathological events associated with brain ischemia are regulate through multiple signaling pathways leading to the activation of oxidative stress process, Ca2+ dyshomeostasis, mitochondrial dysfunction, proinflammatory mediators, excitotoxicity and/or programmed neuronal cell death. Understanding this cascade of molecular events is mandatory in order to develop new therapeutic strategies for stroke. In this review article, we have highlighted the pleiotropic effects of melatonin to counteract the multiple processes of the ischemic cascade. Additionally, experimental evidence supports its actions to ameliorate ischemic long-term behavioural and neuronal deficits, preserving the functional integrity of the blood-brain barrier, inducing neurogenesis and cell proliferation through receptor-dependent mechanism, as well as improving synaptic transmission. Consequently, the synthesis of melatonin derivatives designed as new multitarget-directed products has focused a great interest in this area. This latter has been reinforced by the low cost of melatonin and its reduced toxicity. Furthermore, its spectrum of usages seems to be wide and with the potential for improving human health. Nevertheless, the molecular and cellular mechanisms underlying melatonin´s actions need to be further exploration and accordingly, new clinical studies should be conducted in human patients with ischemic brain pathologies. © 2017 Elsevier Inc.

Herein, we report an ultrasonic promoted facile and convenient “one-pot” procedure for the synthesis of new [1,2,4]triazolo[1,5-a]pyridine derivatives 3, 4 and 5, using Amberlite IRA-400, in short reaction times and high yields and its comparison with classical reaction conditions. The structures of new compounds were assigned with the help of analytical 1H, 13C NMR, and mass spectral studies. © 2017 Taylor & Francis.

Despite more than three decades of intense effort, no anti-Ras therapies have reached clinical application. Contributing to this failure has been an underestimation of Ras complexity and a dearth of structural information. In this regard, recent studies have revealed the highly dynamic character of the Ras surface and the existence of transient pockets suitable for small-molecule binding, opening up new possibilities for the development of Ras modulators. Herein, a novel Ras inhibitor (compound 12) is described that selectively impairs mutated Ras activity in a reversible manner without significantly affecting wild-type Ras, reduces the Ras–guanosine triphosphate (GTP) levels, inhibits the activation of the mitogen-activated protein kinase (MAPK) pathway, and exhibits remarkable cytotoxic activity in Ras-driven cellular models. The use of molecular dynamics simulations and NMR spectroscopy experiments has enabled the molecular bases responsible for the interactions between compound 12 and Ras protein to be explored. The new Ras inhibitor binds partially to the GTP-binding region and extends into the adjacent hydrophobic pocket delimited by switch II. Hence, Ras inhibitor 12 could represent a new compound for the development of more efficacious drugs to target Ras-driven cancers; a currently unmet clinical need. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

A new and unique organocatalytic process for the desymmetrization of meso ferrocene anhydride has been developed. After optimization with a series of quinine, quinidine and squaramide ligands, the method was effective with a 60\% isolated yield and 98\% ee. © 2016 Elsevier Ltd

We report herein an experimental and theoretical study of the Friedländer reaction, from 2-amino-5-chlorobenzaldehyde and ethyl acetoacetate, catalyzed by free-metal nanocatalysts based on carbon aerogels, to afford quinoline 3a. The developed methodology implies the combined use of carbon aerogels with solvent-free technologies under MW irradiation yielding the corresponding quinoline with moderated yield (66\%) in only 5 min of reaction time. Our results demonstrated that the reactivity of the samples upon MW irradiation is strongly dependent on the porosity and surface chemistry of the carbon aerogels, the most active catalytic species being the most acidic oxygenated functional groups, –CO2H groups originated by oxidant treatment, or even in situ by hydrolysis of –CO–O–CO–, over the carbon surface. The theoretical investigation of the reaction mechanism, by using computational methods, demonstrated that the synthesis of quinoline 3a in the absence or in the presence of carbon aerogels takes place by aldolization, subsequent heterocyclization and finally double dehydration. Relatively strong π-π stacking interactions between carbon support and reagents could be behind of the observed catalytic performance also extended for the oxygenated models. Furthermore, the concentration of –CO2H groups over the carbon surface is a key factor favoring each step of the reaction but acting as individual catalytic sites. © 2016 Elsevier B.V.

In the present work, three flavonoids (Fls) namely, quercetin (quer), morin (mor), and primuletin (prim) as well as their metal; (Cu(II) and Fe(III)) complexes (M-Fls) were deposited on APTES-FTO ((3-aminopropyl)triethoxysilane-fluorine doped tin oxide) electrodes. The formation of the (M-)Fls-APTES-FTO surface was verified and characterized through AT-FTIR. These surfaces were found to detect the OH radical at a concentration as low as 2 nM using cyclic and square wave voltammetry and the decrease in the anodic peak currents of (M-)Fls-APTES-FTO working electrodes could be taken as a measure of the OH[rad] radical concentration in the sample. Furthermore, a comparison of the decrease in the peak currents of (M-)Fls-APTES-FTO caused by OH[rad] to the decrease noted in the presence of 100-fold higher concentrations of other reactive oxygen species (ROS including superoxide anion, alkylperoxide anion, singlet oxygen, chlorine monoxide, and hydrogen peroxide), confirmed a high selectivity and rather insignificant interference by other ROS of no more than 4\%. Thus, this method provides significant selectivity in the electrochemical detection of the OH[rad] radical. Among the (M-)Fls tested for hydroxyl radical detection, the most sensitive ones were Fe-quer, Cu-quer and Fe-mor deposited on APTES-FTO. © 2017 Elsevier Ltd

Switchable reactivity through cationic gold-based catalyst control built on the oxidation state, namely cationic Au III versus Au I , has been achieved in the direct functionalization of 2-azetidinone-tethered alkynyl indoles. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Matrix solid-phase dispersion (MSPD) is a simple, fast, rather straightforward and eco-friendly technique for preparation of solid, semisolid, liquid and viscous samples. The feasibility of MSPD for quantitative and selective extraction of both endogenous and exogenous components from matrices with divergent complexity through simple dispersion of the sample constituents in the surface of an appropriated solid support and subsequent elution of the target compounds with a suitable solvent has been demonstrated through a number of application studies. In recent years, progress in MSPD has continued through the incorporation of new engineered and nanotailored sorbents and solvents to the process, its miniaturization and combined use with other enhanced solvent extraction techniques. This chapter discusses basic principles of MSPD, its evolution and last trends in the field through representative application studies dealing with the determination of organic compounds. © 2017 Elsevier B.V.

We report on femtosecond (fs) studies of (E)-2-(2-hydroxybenzyliden) amino-4-nitrophenol (HBA-4NP) in dichloromethane (DCM) and triacetin (TAC) solutions, and within NaX and NaY zeolites. In solution, an ultrafast (≤80 fs) excited-state intramolecular proton-transfer (ESIPT) reaction produces a keto (K) tautomer, which undergoes a rotational process in ∼4 (DCM) and ∼7 ps (TAC) toward the formation of non-emitting structures. Within NaX and NaY, where monomers and aggregates are formed, host-guest and guest-guest interactions play an important role in the ultrafast behaviour of these complexes. These results clearly reflect how nanoconfinement and zeolite composition affect the encapsulated dye photodynamics. © 2017 Elsevier B.V.