Essential factors for control of the equilibrium in the reversible rearrangement of M3N@Ih-C80 fulleropyrrolidines: Exohedral functional groups versus endohedral metal clusters

The effects of exohedral moieties and endohedral metal clusters on the isomerization of M3N@Ih-C80 products from the Prato reaction through [1,5]-sigmatropic rearrangement were systematically investigated by using three types of fulleropyrrolidine derivatives and four different endohedral metal clusters. As a result, all types of derivatives provided the same ratios of the isomers for a given trimetallic nitride template (TNT) as the thermodynamic products, thus indicating that the size of the endohedral metal clusters inside C80 was the single essential factor in determining the equilibrium between the [6,6]-isomer (kinetic product) and the [5,6]-isomer. In all the derivatives, the [6,6]- and [5,6]-Prato adducts with larger metal clusters, such as Y3N and Gd3N, were equally stable, which is in good agreement with DFT calculations. The reaction rate of the rearrangement was dependent on both the substituent of exohedral functional groups and the endohedral metal-cluster size. Further DFT calculations and 13C NMR spectroscopic studies were employed to rationalize the equilibrium in the rearrangement between the [6,6]- and [5,6]-fulleropyrrolidines

3,4-Methylenedioxymethamphetamine enhances kainic acid convulsive susceptibility

Abstract Kainic acid (KA) causes seizures and neuronal loss in the hippocampus. The present study investigated whether a recreational schedule of 3,4-methylenedioxymethamphetamine (MDMA) favours the development of a seizure state in a model of KA-induced epilepsy and potentiates the toxicity profile of KA (20 or 30 mg/kg). Adolescent male C57BL/6 mice received saline or MDMA t.i.d. (s.c. every 3 h), on 1 day a week, for 4 consecutive weeks. Twenty-four hours after the last MDMA exposure, the animals were injected with saline or KA (20 or 30 mg/kg). After this injection, we evaluated seizures, hippocampal neuronal cell death, microgliosis, astrogliosis, and calcium binding proteins. MDMA pretreatment, by itself, did not induce neuronal damage but increased seizure susceptibility in all KA treatments and potentiated the presence of Fluoro-Jade-positive cells in CA1. Furthermore, MDMA, like KA, significantly decreased parvalbumin levels in CA1 and dentate gyrus, where it potentiated the effects of KA. The amphetamine derivative also promoted a transient decrease in calbindin and calretinin levels, indicative of an abnormal neuronal discharge. In addition, treatment of cortical neurons with MDMA (1050 μM) for 6 or 48 h significantly increased basal Ca2 +, reduced basal Na+ levels and potentiated kainate response. These results indicate that MDMA potentiates KA-induced neurodegeneration and also increases KA seizure susceptibility. The mechanism proposed includes changes in Calcium Binding Proteins expression, probably due to the disruption of intracellular ionic homeostasis, or/and an indirect effect through glutamate release.

Synthesis and characterization of new amino acyl-4-thiazolidones

A series of heterocyclic compounds with a 4-thiazolidone nucleus and amino acyl moiety were synthesized by protection reaction of thiosemicarbazide using the symmetrical anhydride (Boc)2O and cyclization with chloroacetic acid under mild conditions. Trifluoroacetic acid was used to obtain 4-thiazolidone and the alpha-amino acid condensation reactions were carried out using strategies for peptide synthesis. The characterization of this new class of compounds was performed using IR and ¹H-NMR spectroscopy.

Reações de 1,2-dicloro-4,5-dinitrobenzeno com aminas: monossubstituição de nitro e dissubstituição de cloro e nitro

1,2-dichloro-4,5-dinitrobenzene (DCDNB) reacts with primary and secondary amines, in acetonitrile, at room temperature, to give a monosubstituted nitro product with a yield of 85 to 95%. The chloro-nitro-disubstituted product is formed with excess amine under reflux. Piperidine, pyrroline, dimethylamine and methylamine were the most reactive reagents in both mono- and disubstitution.

3,4-Methylenedioxymethamphetamine enhances kainic acid convulsive susceptibility

Abstract Kainic acid (KA) causes seizures and neuronal loss in the hippocampus. The present study investigated whether a recreational schedule of 3,4-methylenedioxymethamphetamine (MDMA) favours the development of a seizure state in a model of KA-induced epilepsy and potentiates the toxicity profile of KA (20 or 30 mg/kg). Adolescent male C57BL/6 mice received saline or MDMA t.i.d. (s.c. every 3 h), on 1 day a week, for 4 consecutive weeks. Twenty-four hours after the last MDMA exposure, the animals were injected with saline or KA (20 or 30 mg/kg). After this injection, we evaluated seizures, hippocampal neuronal cell death, microgliosis, astrogliosis, and calcium binding proteins. MDMA pretreatment, by itself, did not induce neuronal damage but increased seizure susceptibility in all KA treatments and potentiated the presence of Fluoro-Jade-positive cells in CA1. Furthermore, MDMA, like KA, significantly decreased parvalbumin levels in CA1 and dentate gyrus, where it potentiated the effects of KA. The amphetamine derivative also promoted a transient decrease in calbindin and calretinin levels, indicative of an abnormal neuronal discharge. In addition, treatment of cortical neurons with MDMA (1050 μM) for 6 or 48 h significantly increased basal Ca2 +, reduced basal Na+ levels and potentiated kainate response. These results indicate that MDMA potentiates KA-induced neurodegeneration and also increases KA seizure susceptibility. The mechanism proposed includes changes in Calcium Binding Proteins expression, probably due to the disruption of intracellular ionic homeostasis, or/and an indirect effect through glutamate release.

Seeing smells: development of an optoelectronic nose

The development of an array of chemically-responsive dyes on a porous membrane and in its use as a general sensor for odors and volatile organic compounds (VOCs) is reviewed. These colorimetric sensor arrays (CSA) act as an "optoelectronic nose" by using an array of multiple dyes whose color changes are based on the full range of intermolecular interactions. The CSA is digitally imaged before and after exposure and the resulting difference map provides a digital fingerprint for any VOC or mixture of odorants. The result is an enormous increase in discriminatory power among odorants compared to prior electronic nose technologies. For the detection of biologically important analytes, including amines, carboxylic acids, and thiols, high sensitivities (ppbv) have been demonstrated. The array is essentially non-responsive to changes in humidity due to the hydrophobicity of the dyes and membrane.

Relação entre transferência de carga e as interações intermoleculares em complexos de hidrogênio heterocíclicos

Hydrogen-bonded complexes formed by the interaction of the heterocyclic molecules C2H4O and C2H5N with HF, HCN, HNC and C2H2 have been studied using density functional theory. The hydrogen bond strength has been analyzed through electron density charge transfer from the proton acceptor to the proton donor. The density charge transfer has been estimated using different methods such as Mulliken population analysis, CHELPG, GAPT and AIM. It has been shown that AIM-estimated charge transfer correlates very well with the hydrogen bond energy and the infrared bathochromic effect of the proton donor stretching frequencies.

Thioflavin-S staining of bacterial inclusion bodies for the fast, simple, and inexpensive screening of amyloid aggregation inhibitors

Amyloid aggregation is linked to a large number of human disorders, from neurodegenerative diseases as Alzheimer"s disease (AD) or spongiform encephalopathies to non-neuropathic localized diseases as type II diabetes and cataracts. Because the formation of insoluble inclusion bodies (IBs) during recombinant protein production in bacteria has been recently shown to share mechanistic features with amyloid self-assembly, bacteria have emerged as a tool to study amyloid aggregation. Herein we present a fast, simple, inexpensive and quantitative method for the screening of potential anti-aggregating drugs. This method is based on monitoring the changes in the binding of thioflavin-S to intracellular IBs in intact Eschericchia coli cells in the presence of small chemical compounds. This in vivo technique fairly recapitulates previous in vitro data. Here we mainly use the Alzheimer"s related beta-amyloid peptide as a model system, but the technique can be easily implemented for screening inhibitors relevant for other conformational diseases simply by changing the recombinant amyloid protein target. Indeed, we show that this methodology can be also applied to the evaluation of inhibitors of the aggregation of tau protein, another amyloidogenic protein with a key role in AD.

1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

Um estudo teórico relativo à não-linearidade da ligação de hidrogênio em sistemas heterocíclicos C2H4O-C2H2 e C2H4S-C2H2

B3LYP/6-31G(d,p) calculations were used to determine the optimized geometries of the C2H4O-C2H2 and C2H4S-C2H2 heterocyclic hydrogen-bonded complexes. Results of structural, rotational, electronic and vibrational parameters indicate that the hydrogen bonding is non-linear due to the pi bond of the acetylene interacting with the hydrogen atoms of the methyl groups of the three-membered rings. Moreover, the theoretical investigation showed that the non-linearity is much more intriguing, since there is a structural disjunction on the acetylene within the heterocyclic system.

1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

Thioflavin-S staining of bacterial inclusion bodies for the fast, simple, and inexpensive screening of amyloid aggregation inhibitors

Amyloid aggregation is linked to a large number of human disorders, from neurodegenerative diseases as Alzheimer"s disease (AD) or spongiform encephalopathies to non-neuropathic localized diseases as type II diabetes and cataracts. Because the formation of insoluble inclusion bodies (IBs) during recombinant protein production in bacteria has been recently shown to share mechanistic features with amyloid self-assembly, bacteria have emerged as a tool to study amyloid aggregation. Herein we present a fast, simple, inexpensive and quantitative method for the screening of potential anti-aggregating drugs. This method is based on monitoring the changes in the binding of thioflavin-S to intracellular IBs in intact Eschericchia coli cells in the presence of small chemical compounds. This in vivo technique fairly recapitulates previous in vitro data. Here we mainly use the Alzheimer"s related beta-amyloid peptide as a model system, but the technique can be easily implemented for screening inhibitors relevant for other conformational diseases simply by changing the recombinant amyloid protein target. Indeed, we show that this methodology can be also applied to the evaluation of inhibitors of the aggregation of tau protein, another amyloidogenic protein with a key role in AD.

1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

Sílica quimicamente modificada com os grupos p-anisidina, p-fenitidina e p-fenilenodiamina usada como adsorvente para Pb2+, Cu2+, Cd2+ e Ni2+ em soluções aquosa e etanólica

Silica gel was chemically modified with the aromatic amines p-anisidine, p-phenytidine and p-phenylenediamine, using grafting reactions. The resulting modified silicas were characterized by infrared spectroscopy and N2 adsorption/desorption isotherms. The organic groups were covalently immobilized in a monolayer form. These modified silicas were investigated as adsorbents for Pb2+, Cu2+, Cd2+ and Ni2+ in aqueous and ethanol solutions. In a general way, the adsorption capacity values for all adsorbents presented the following sequence: Pb2+ >> Cu2+ @Cd2+ @ Ni2+. Adsorption studies for all adsorbents, in competitive medium, showed better selectivity for Cu2+ and Pb2+ in aqueous medium and for Pb2+ in ethanol solution. Desorption studies were carried out using HCl and HNO3 as eluents.

Rota hidrometalúrgica de recuperação de molibdênio, cobalto, níquel e alumínio de catalisadores gastos de hidrotratamento em meio ácido

This work describes a hydrometallurgical route for processing spent commercial catalysts (CoMo and NiMo/Al2O3). Samples were preoxidized (500 ºC, 5 h) in order to eliminate coke and other volatile species present. The calcined solid was dissolved in concentrated H2SO4 and water (1:1 vol/vol) at 90 ºC; the insoluble matter was separated from the solution. Molybdenum was recovered by solvent extraction using tertiary amines at pH around 1.8. Cobalt (or nickel) was separated by addition of aqueous ammonium oxalate at the above pH. Phosphorus was removed by passing the liquid through a strong anion exchange column. Aluminum was recovered by neutralizing the solution with NaOH. The route presented in this work generates less final aqueous wastes because it is not necessary to use alkaline medium during the metal recovery steps.