Asymmetric Organocatalyzed Aza-Henry Reaction of Hydrazones: Experimental and Computational Studies.

The first asymmetric catalyzed aza-Henry reaction of hydrazones is presented. In this process, quinine was used as the catalyst to synthesize different alkyl substituted ß-nitrohydrazides with ee up to 77 %. This ee was improved up to 94 % by a further recrystallization and the opposite enantiomer can be obtained by using quinidine as the catalyst, opening exciting possibilities in fields in which the control of chirality is vital, such as the pharmaceutical industry. Additionally, experimental and ab initio studies were performed to understand the reaction mechanism. The experimental results revealed an unexpected secondary kinetic isotope effect (KIE) that is explained by the calculated reaction pathway, which shows that the protonation of the initial hydrazone and the C-C bond forming reaction occur during a concerted process. This concerted mechanism makes the catalysis conceptually different to traditional base-promoted Henry and aza-Henry reactions.

Magnetic Structures of Mn11Ta4O21 and Interpretation as an Hexagonal A-site Manganite.

Mn11Ta4O21 is presented as the first hexagonal A-site manganite. Based on simple rules, the structure is compatible with a 14H-layer (cchchch)2 stacking sequence that is related to BaVO3 and BaCrO3 high-pressure polymorphs. The A-site overstoichiometry is explained through difference in ionic radii sizes between Ba and Mn. Magnetic properties show two transitions at TN1 = 88 K and TN2 = 56 K. Neutron powder diffraction evidence two magnetic structures with purely antiferromagnetic and ferrimagnetic orders below TN1 and TN2, respectively. A complementary description with 14H-(hhccccc)2 sequence of only Mn octahedra provides a direct comparison with BaMnO3-δ hexagonal perovskites and naturally explains the AFM order. Below TN2 a magneto-elastic coupling along with uniaxial negative thermal expansion are observed.

Novel ureido-dihydropyridine scaffolds as theranostic agents.

In this work, the synthesis of interesting urea derivatives 5 based on 1,4-dihydropyridines 3 is described for the first time. Considering that both families exhibit potential as drugs to treat various diseases, their activity as anticancer agents has been evaluated in HeLa (cervix), Jurkat (leukaemia) and A549 (lung) cancer cell lines as well as on healthy mice in vivo. In general, whereas 1,4-dihydropyridines show a moderate cytotoxic activity, their urea analogues cause an extraordinary increase in their antiproliferative activity, specially towards HeLa cells. Because of the chiral nature of these compounds, enantiomerically enriched samples were also tested, showing different cytotoxic activity than the racemic mixture. Although the reason is not clear, it could be caused by a complex amalgam of physical and chemical contributions. The studied compounds also exhibit luminescent properties, which allow performing a biodistribution study in cancer cells. They have emission maxima between 420 and 471 nm, being the urea derivatives in general red shifted. Emission quenching was observed for those compounds containing a nitro group (3e,f and 5e,f). Fluorescence microscopy showed that 1,4-dihydropyridines 3a and 3g localised in the lysosomes, in contrast to the urea derivatives 5h that accumulated in the cell membrane. This different distribution could be key to explain the differences found in the cytotoxic activity and in the mechanism of action. Interestingly, a preliminary in vivo study regarding the acute toxicity of some of these compounds on healthy mice has been conducted, using a concentration up to 7200 times higher than the corresponding IC50 value. No downgrade in the welfare of the tested mice was observed, which could support their use in preclinical tumour models.

Effects of Bisphenol A on Foxl2 gene expression and DNA damage in adult viviparous fish Goodeaatripinnis.

Bisphenol A (BPA) is an emerging pollutant of global concern. Viviparous fish Goodea atripinnis is endemic to the Central Mexican Plateau where BPA was detected; however, few studies examined the influence of this chemical on native viviparous fish. The effects of BPA (sublethal dose) were determined on DNA integrity and Foxl2 expression in G. atripinnis gonads, and interactions of BPA with FOXL2 protein. Genotoxicity analysis revealed that % comets, at 14 and 28 days and comet tail length (at 14 days) were significantly higher in exposed compared to controls. In general, the % DNA tail was not markedly higher in BPA-treated fish; however, tail moment related to tail length exhibited significant increases in DNA damage. RT-qPCR assays showed Foxl2 overexpression after 14 and 28 days of exposure in females; while in males, Foxl2 was overexpressed after 28 days. In silico analysis demonstrated that BPA interacted with seven residues located in FOXL2 homeodomain. In summary, sublethal BPA doses induced DNA damage and changes in Foxl2 expression in gonadal cells of G. atripinnis, which may adversely affect reproduction in BPA-exposed wild populations. Foxl2 overexpression and BPA-FOXL2 interaction suggested alterations in processes involving Foxl2. Viviparous fish may thus serve as potential non-conventional models for assessing pollutants effects.

First Organocatalytic Asymmetric Synthesis of 1-Benzamido-1,4-Dihydropyridine Derivatives.

Preliminary results concerning the first asymmetric synthesis of highly functionalized 1-benzamido-1,4-dihydropyridine derivatives via the reaction of hydrazones with alkylidenemalononitriles in the presence of ß-isocupreidine catalyst are reported. The moderate, but promising, enantioselectivity observed (40⁻54% ee), opens the door to a new area of research for the asymmetric construction of new chiral 1,4-dihydropyridine derivatives, whose enantioselective catalytic preparation are still very limited. Moreover, the use of hydrazones for the enantioselective construction of chiral 1,4-dihydropyridines has been overlooked in the literature so far. Therefore, our research represents a pivotal example in this field which remains still unexplored.

Synthesis and supramolecular self-assembly of glutamic acid-based squaramides.

We describe the preparation and characterization of two new unsymmetrical squaramide-based organogelators. The synthesis of the compounds was carried out by subsequent amine condensations starting from dimethyl squarate. The design of the gelators involved a squaramide core connected on one side to a long aliphatic chain and on the other side to a glutamic acid residue. The gelator bearing the free carboxylic groups showed a lower gelation capacity than its precursor diester derivative. Some selected gels were further studied by infrared spectroscopy, rheology and electron microscopy. Critical gelation concentrations and gel-to-sol transition temperatures were also determined for each case. In addition, the superior squaramide diester gelator was compared with an analogue triazole-based gelator in terms of critical gelation concentration, gelation kinetics and thermal phase transition.

Optimizing the Accuracy and Computational Cost in Theoretical Squaramide Catalysis: The Henry Reaction.

This study represents the first example where the accuracy of different combinations of density functional theory (DFT) methods and basis sets have been compared in squaramide catalysis. After an optimization process of the precision obtained and the computational time required in the computational calculations, highly precise results were achieved compared to the experimental outcomes while requiring the least amount of time possible. Here, we have explored computationally and experimentally the mechanism of the squaramide-catalyzed Henry reaction. This is a complex reaction of about 100 atoms and a great number of diverse non-covalent interactions. Moreover, this research is one of the scarce examples where the organocatalyst acts in a trifunctional manner and is the first investigation in which a trifunctional squaramide catalyst has been employed. Functional ωB97X-D showed the best results when used with different versions of the 6-311 basis sets, leading to highly accurate calculations of the outcomes of the Henry reaction when using nine aldehydes with different structural characteristics. Furthermore, in these relatively large systems, the use of a split-valence triple-zeta basis set saves a large amount of time compared with using larger basis sets that are sometimes employed in organocatalytic studies, such as the TZV and Def2TZV basis set families.

Asymmetric Organocatalytic Synthesis of Substituted Chiral 1,4-Dihydropyridine Derivatives.

The first cinchona-alkaloid-organocatalyzed enantioselective synthesis of chiral 1,4-dihydropyridine derivatives is described. Bis-cinchona catalyst 3b activates the Michael addition reaction between malononitrile derivatives 2 and enamines 1, affording the appealing and highly substituted 1,4-dihydropyridines 4 with very good results in most cases. This is one of very few examples of the synthesis of chiral 1,4-dihydropyridines by an enantioselective catalytic procedure. The highly substituted final compounds are of interest for their potential biological activity. This efficient protocol opens the door to a new area of research for the asymmetric construction of these skeletons for which enantioselective syntheses are still very limited.

Biological Responses of the American Coot (Fulica americana), in wetlands with contrasting environmental conditions (Basin of México).

Wetland ecosystems are subject to severe impacts (physical and chemical) and to the input of various xenobiotics that provoke toxicological consequences. Waterbirds are potential sentinel species of these environments. To analyze how habitat conditions affect the health of Fulica americana, early-warning biomarkers, histopathology, somatic indices, and water quality were examined in two wetlands of the Basin of Mexico: Xochimilco, an urban wetland highly eutrophic with a mixture of pollutants, and Tecocomulco (the reference site), a rural wetland with hunting migratory birds in winter, and with some agricultural contaminants. Coots were collected over 1 year, and the birds were aged, eviscerated, and weighed. Liver samples were analyzed biochemically and histologically. Biomarkers revealed that coots displayed higher lipid peroxidation and elevated activities of gamma-glutamyl transferase and alanine aminotransferase, suggesting hepatic damage during autumn and winter. In Tecocomulco, coots during winter has the highest thiobarbituric acid reactive substances (as a measure of oxidative stress), which may be associated with the presence of predators. In Tecocomulco, the higher gonadosomatic index was detected in spring and summer, while in Xochimilco it was elevated in summer, indicating a delayed egg laying and reproduction in coots from the latter study site. In both wetlands, leukocyte infiltration, alone or combined with vasocongestion, reflected alterations in the inflammatory processes in liver throughout the annual cycle and thus potentially altered hepatic function and organism survival. In both wetlands, coots were permanent residents and chronically exposed to different stressors, suggesting damage may be irreversible with potentially adversely reproductive consequences.

Self-assembled fibrillar networks of a multifaceted chiral squaramide: supramolecular multistimuli-responsive alcogels.

Chiral N,N'-disubstituted squaramide has been found to undergo self-assembly in a variety of alcoholic solvents at low concentrations leading to the formation of novel nanostructured supramolecular alcogels. The gels responded to thermal, mechanical, optical and chemical stimuli. Solubility studies, gelation ability tests and computer modeling of a series of structurally related squaramides proved the existence of a unique combination of non-covalent molecular interactions and favorable hydrophobic/hydrophilic balance in that drive the anisotropic growth of alcogel networks. The results have also revealed a remarkable effect of ultrasound on both the gelation kinetics and the properties of the alcogels.

Predicting mortality in burn patients with bacteraemia.

OBJECTIVE: To determine factors associated with mortality in burn patients with bacteraemia. BACKGROUND: Previous studies have shown the negative impact of bacteraemia on the prognosis of burn patients, but only a few of these have analysed variables intervening in the clinical progress of these patients. METHODS: A retrospective study of adult burn patients (n = 73) with bacteraemia (103 episodes) in a Burns Unit during the 2000-2013 period. The study collected demographic variables, and comorbidity, injury-related and clinical data related to bacteraemia. Variables related to hospital mortality were analysed using a multiple logistic regression model. RESULTS: The cumulative incidence of bacteraemia was 4.4 episodes/100 patients. The mean age was 53.3 ± 19.2 years (65.8 % male). The median total body surface area (TBSA) was 35 %, while 50.7 % of the population had inhalation syndrome. The mean SOFA score at the onset of bacteraemia was 2.7 ± 3.8. The most common pathogen was Pseudomonas aeruginosa (17.5 %). The mortality rate was 24.7 %. The variables that were significantly associated with mortality were age (OR = 1.13), TBSA (OR = 1.05), SOFA score at the onset of bacteraemia (OR = 1.53) and recurrent bacteraemia (OR = 41.6). CONCLUSION: In addition to conventional risk factors, recurrence and organ dysfunction at the onset of bacteraemia are also associated with mortality, while the pathogen involved is not a prognostic factor.

Fluoride Anion Recognition by a Multifunctional Urea Derivative: An Experimental and Theoretical Study.

In this work we demonstrate the ability of a multifaceted N,N'-disubstituted urea to selectively recognize fluoride anion (F(-)) among other halides. This additional function is now added to its already reported organocatalytic and organogelator properties. The signaling mechanism relies on the formation of a charge-transfer (CT) complex between the urea-based sensor and F¯ in the ground state with a high association constant as demonstrated by absorption and fluorescence spectroscopy. The nature of the hydrogen bonding interaction between the sensor and F¯ was established by ¹H-NMR studies and theoretical calculations. Moreover, the recovery of the sensor was achieved by addition of methanol.

Liver histological changes and lipid peroxidation in the amphibian Ambystoma mexicanum induced by sediment elutriates from the Lake Xochimilco.

Lacustrine sediments accumulate pollutants that input from the lake watershed and can be released to the water column by sediment resuspension; thus, pollutants can change their bioavailability and exert adverse effects to aquatic biota. Shallow-urban lakes are particularly susceptible to receive pollutants from urban discharges and sediment resuspension. Lake Xochimilco, in Mexico City, an urban-shallow lake, faces multiple problems: urban sprawl, overexploitation of aquifers, drying of springs, discharge of wastewater from treatment plants, and sediment resuspension. The aquatic biota living in this ecosystem is continuously exposed to the release of pollutants from the sediments. We assessed the risk that pollutants released from sediments from Lake Xochimilco, Touristic (TZ) and Agriculture zone (AZ), can exert on a native amphibian species of the lake (Ambystoma mexicanum) through exposure bioassays to sediment elutriates. We evaluate alterations in the amphibian by three approaches: biochemical (level of lipid peroxidation, LPO), cellular (ultrastructure) and the liver histology of A. mexicanum and we compare them with a batch control. Additionally, we assessed heavy metals (Pb, Cd and Hg) in elutriates. Elutriates from TZ showed the highest concentrations of the metals assessed. Organisms exposed to sediment elutriates from either study sites showed higher LPO values than control organisms (p<0.05). Organisms exposed to elutriates from the TZ showed the most conspicuous damages: hepatic vasodilation of sinusoids, capillaries with erythrocytes, leukocyte infiltration and cytoplasmic vacuolation in hepatocytes. The biological responses assessed reflected the risk that faces A. mexicanum when is exposed for prolonged periods to sediment resuspension in Lake Xochimilco.

The aminoindanol core as a key scaffold in bifunctional organocatalysts.

The 1,2-aminoindanol scaffold has been found to be very efficient, enhancing the enantioselectivity when present in organocatalysts. This may be explained by its ability to induce a bifunctional activation of the substrates involved in the reaction. Thus, it is easy to find hydrogen-bonding organocatalysts ((thio)ureas, squaramides, quinolinium thioamide, etc.) in the literature containing this favored structural core. They have been successfully employed in reactions such as Friedel-Crafts alkylation, Michael addition, Diels-Alder and aza-Henry reactions. However, the 1,2-aminoindanol core incorporated into proline derivatives has been scarcely explored. Herein, the most representative and illustrative examples are compiled and this review will be mainly focused on the cases where the aminoindanol moiety confers bifunctionality to the organocatalysts.

New Organocatalytic Asymmetric Synthesis of Highly Substituted Chiral 2-Oxospiro-[indole-3,4'- (1',4'-dihydropyridine)] Derivatives.

Herein, we report our preliminary results concerning the first promising asymmetric synthesis of highly functionalized 2-oxospiro-[indole-3,4'-(1',4'-dihydropyridine)] via the reaction of an enamine with isatylidene malononitrile derivatives in the presence of a chiral base organocatalyst. The moderate, but promising, enantioselectivity observed (30%-58% ee (enantiomeric excess)) opens the door to a new area of research for the asymmetric construction of these appealing spirooxindole skeletons, whose enantioselective syntheses are still very limited.

Toxicity induced by dieldrin and chlorpyrifos in the freshwater crayfish Cambarellus montezumae (Cambaridae).

The toxicity induced by insecticides in aquatic organisms is of utmost relevance because it may give a clue about the degree of health or damage of the involved ecosystem. In the present report, we determined the effect of dieldrin (DD) and chlorpyrifos (CP) on the freshwater crayfish, Cambarellus montezumae. The organisms (4-6 cm in diameter) were collected in the Ignacio Ramirez Reservoir, situated at 50 km Northeast of Mexico City, in the Rio Lerma Basin. Initially, we determined the LC50 value with the Probit method, then the DNA damage with single cell gel electrophoresis (comet assay applied at 24, 48, and 72 h of exposure) to the brain and hepatopancreas of animals exposed (in reconstituted water) to 0.05 and 0.5 microg/L of each insecticide. In the hepatopancreas of the same organisms, we determined the lipid peroxidation by applying the TBARS test. DNA damage and lipid peroxidation were also evaluated with the same methods to organisms exposed in water from the reservoir. In regard to the LC50, at 72 h of exposure, we found a value of 5.1 microg/L and a value of 5.62 microg/L for DD and CP, respectively. The comet assay applied at different exposure times showed significant DNA damage to both organs, with respect to the control level. In the case of DD, statistical significance was observed for the two doses in the whole evaluated schedule. CP was genotoxic in the brain with the high dose at 72 h, and in the hepatopancreas with the two tested doses at all evaluated exposure times. Also, a significant lipid peroxidation increase was detected with the two doses of insecticides. In the study with water from the reservoir, a more pronounced DNA damage was detected. Our results showed strong DNA damage induced by both insecticides in the crayfish, as well as a correlation with the lipid peroxidation effect, suggesting that oxidative stress is involved in the genotoxic alteration. Our results also showed the usefulness of the studied organism as well as the applied tests for the evaluation of toxicological effects, and suggested the pertinence of applying the comet assay to other freshwater organisms to evaluate the bioaccumulation of insecticides.

Tracheostomy in the management of patients with thermal injuries.

OBJECTIVE: To assess the use and clinical impact of tracheostomy in burn patients. SUMMARY BACKGROUND DATA: The role of tracheostomy in the management of burn patients is controversial, with only a few recent studies conducted in this population. METHODS: Retrospective study of all adult burn patients who underwent a tracheostomy in a Burns Unit between 1995 and 2013. These were compared with a control group (1:1) who underwent orotracheal intubation. Hospital records were reviewed to obtain demographic and clinical information, including those related to respiratory support and tracheostomy. The McNemar's Chi-square and Signed-Rank Tests were used to study differences in morbimortality between both groups. RESULTS: A total of n = 20 patients underwent tracheostomy (0.9% of admissions, 56.0 ± 19.5 years, 60.0% women). The most common indication was long-term ventilation (75%), 24.6 ± 19.7 days after admission. Thirteen patients were successfully decannulated with a fatal complication observed in one case. Patients in the tracheostomy group were found to require longer-term mechanical ventilation (43.2 vs. 20.4 days; P = 0.004), with no differences in respiratory infection rates (30.0% vs. 31.6%; P = 0.687) or mortality (30.0% vs. 42.1%; P = 0.500). Ventilator weaning times (15.7 vs. 3.3 days; P = 0.001) and hospital stays (99.1 vs. 53.1 days; P = 0.030) were longer in the tracheostomy group, with no differences in duration of sedation. CONCLUSIONS: Tracheostomy may be a safe procedure in burn patients and is not associated with higher rates of mortality or respiratory infection. Tracheostomy patients showed longer mechanical ventilation times and higher morbidity, probably not attributable to tracheostomy.

Exploiting molecular self-assembly: from urea-based organocatalysts to multifunctional supramolecular gels.

We describe the self-assembly properties of chiral N,N'-disubstituted urea-based organocatalyst 1 that leads to the formation of hierarchical supramolecular gels in organic solvents at low concentrations. The major driving forces for the gelation are hydrogen bonding and π-π interactions according to FTIR and (1)H NMR spectroscopy, as well as quantum-mechanical studies. The gelation scope could be interpreted based on Kamlet-Taft solvatochromic parameters. TEM, SEM, and AFM imaging revealed that a variety of morphologies including helical, laths, porous, and lamellar nanostructures could be obtained by varying the solvent. Experimental gelation tests and computational structural analysis of various structurally related compounds proved the existence of a unique set of molecular interactions and an optimal hydrophilic/hydrophobic balance in 1 that drive the formation of stable gels. Responses to thermal, mechanical, optical, and chemical stimuli, as well as multifunctionality were demonstrated in some model gel materials. Specifically, 1 could be used for the phase-selective gelation of organic solvent/water mixtures. The gel prepared in glycerol was found to be thixotropic and provided a sensitive colorimetric method for the detection of Ag(I) ions at millimolar concentrations in aqueous solution. Moreover, the gel matrix obtained in toluene served as a nanoreactor for the Friedel-Crafts alkylation of 1H-indole with trans-ß-nitrostyrene.

A Friedel-Crafts alkylation mechanism using an aminoindanol-derived thiourea catalyst.

Computational calculations based on experimental results shed light on the mechanistic proposal for a Friedel-Crafts alkylation reaction between indole and nitroalkenes, catalysed by a chiral aminoindanol-derived thiourea. In our hypothesis both substrates are simultaneously coordinated to the catalyst in a bifunctional mode. This study elucidates the crucial role played by the hydroxyl group of the catalyst in the success of the reaction. The OH group seems to be involved in the preferential attack of the indole over the nitroalkene, affording the major enantiomer and stabilizing the resulting transition state by a concomitant coordination with the nitroolefin. The results obtained with other catalysts from the same family, and other indoles, are reported and discussed. Theoretical calculations are in agreement with the experimental outcomes and with our previously developed mechanism, displaying the pivotal role played by hydrogen bond interactions.

Organocatalytic enantioselective hydrophosphonylation of aldehydes.

We report our results concerning the first squaramide-catalysed hydrophosphonylation of aldehydes. In all cases, the reactions proceeded smoothly and cleanly under mild reaction conditions rendering final α-hydroxy phosphonates in very good yields and high enantioselectivities. It is one of the few organocatalytic examples of this reaction using aldehydes. It is the first time that diphenylphosphite (1e) has been successfully employed in a chiral Pudovik reaction with aldehydes, in contrast to the dialkylphosphites used in previously published procedures, extending the generality of this asymmetric methodology.