Cascade Synthesis of New Indole-Containing Pentacyclic Scaffolds Mediated by Aryl and Iminyl Radicals.

A five-step approach, starting from simple 1,5-disubstituted indoles, has been implemented for the synthesis of diversely substituted indole-pyrido-indene pentacyclic compounds up to 54 % yield via domino radical-mediated processes in the presence of the radical reagents DLP/TTMSS and AIBN/TTMSS. Reactions proceeded with diverse key starting radical cyano-precursors strategically synthesized which were subsequently transformed into the target pentacyclic compounds through an aryl/iminyl radical-mediated domino reactions sequence. In addition to the routine spectroscopic techniques, the structure of radical precursors, as well as, the target pentacyclic products were unequivocally established by single crystal X-ray diffraction, confirming the effectiveness of the proposed synthetic sequence.

Experimental and theoretical study of the mechanism and rate constants of the sequential 5-exo-trig spirocyclization involving vinyl, aryl and N-alkoxyaminyl radicals.

In this research the sequential generation and cyclization of N-alkoxyaminyl radicals to produce 1-azaspiro[4.4]nonane, a prominent scaffold in organic and medicinal chemistry, was studied. Competition experiments in benzene at 80 °C with brominated oxime ethers using Bu3SnH as chain transfer and AIBN as the initiator generated vinyl or aryl radicals which were captured by oxime ethers, allowing approximate 5-exo-trig cyclization constants at 4.6 × 108 s-1 and 9.9 × 108 s-1 respectively to be established. Similar results were obtained by kinetic studies using the transition state theory (TST) from ab initio calculations with density functional theory (DFT) using the M06-2X, B3LYP, mPW1PW91 and TPSSh functionals in combination with the 6-311+G(d, p) basis set. Additionally, it was found that the 5-exo-trig cyclization of the N-alkoxyaminyl radical onto CC double bonds is a reversible process whose constants were determined to be in the range of 6.2 × 100 s-1 and 3.5 × 106 s-1 at 80 °C, depending on the nature of the substituents. The calculation of the radical stabilization energy (RSE) shows that the N-alkoxyaminyl radical is a very stable species and its reactivity in the addition on alkenes is governed by its nucleophilic character and the stability of the carbon-centered radical formed after cyclization. The reduction constant of the N-alkoxyaminyl radical with Bu3SnH in the gas phase at 80 °C was also estimated to be 3.4 × 100 M-1 s-1 through computational calculations. This information facilitates the rational planning of cascades and other methodologies applied to the construction of carbocyclic and aza-heterocyclic compounds.

Synthesis of 1-Azaspiro[4.4]nonane Derivatives Enabled by Domino Radical Bicyclization Involving Formation and Capture of Alkoxyaminyl Radicals.

The application of a domino radical bicyclization for the synthesis of compounds containing the 1-azaspiro[4.4]nonane skeleton in 11-67% yields as a mixture of diastereomers is described (trans configuration preference). This process involved formation and capture of alkoxyaminyl radicals. For this purpose, O-benzyl oxime ethers with a brominated or iodinated aromatic ring or a terminal alkynyl group and an alkenyl moiety were employed as starting materials. The bicyclization was initiated by 2,2'-azobisisobutyronitrile or triethylborane and promoted by Bu3SnH. The best results were obtained with O-benzyl oxime ethers containing an alkenyl moiety tethered to electron withdrawing groups or aryl substituents, whereas oxime radical precursor attached to methyl-substituted olefin precluded the capture of alkoxyaminyl radical, giving rise mainly to monocyclized product.

Exploring Biogeochemistry and Microbial Diversity of Extant Microbialites in Mexico and Cuba.

Microbialites are modern analogs of ancient microbial consortia that date as far back as the Archaean Eon. Microbialites have contributed to the geochemical history of our planet through their diverse metabolic capacities that mediate mineral precipitation. These mineral-forming microbial assemblages accumulate major ions, trace elements and biomass from their ambient aquatic environments; their role in the resulting chemical structure of these lithifications needs clarification. We studied the biogeochemistry and microbial structure of microbialites collected from diverse locations in Mexico and in a previously undescribed microbialite in Cuba. We examined their structure, chemistry and mineralogy at different scales using an array of nested methods including 16S rRNA gene high-throughput sequencing, elemental analysis, X-Ray fluorescence (XRF), X-Ray diffraction (XRD), Scanning Electron Microscopy-Energy Dispersive Spectroscopy (SEM-EDS), Fourier Transformed Infrared (FTIR) spectroscopy and Synchrotron Radiation-based Fourier Transformed Infrared (SR-FTIR) spectromicroscopy. The resulting data revealed high biological and chemical diversity among microbialites and specific microbe to chemical correlations. Regardless of the sampling site, Proteobacteria had the most significant correlations with biogeochemical parameters such as organic carbon (Corg), nitrogen and Corg:Ca ratio. Biogeochemically relevant bacterial groups (dominant phototrophs and heterotrophs) showed significant correlations with major ion composition, mineral type and transition element content, such as cadmium, cobalt, chromium, copper and nickel. Microbial-chemical relationships were discussed in reference to microbialite formation, microbial metabolic capacities and the role of transition elements as enzyme cofactors. This paper provides an analytical baseline to drive our understanding of the links between microbial diversity with the chemistry of their lithified precipitations.

Design, synthesis and crystallographic study of novel indole-based cyano derivatives as key building blocks for heteropolycyclic compounds of major complexity.

A four-stage reaction sequence has been designed and developed for the synthesis of highly functionalized enolate esters as key building blocks for the synthesis of novel heteropolycyclic compounds of potential pharmaceutical value. The sequence starts with simple commercially available indoles and proceeds via 3-(indol-3-yl)-3-oxopropanenitriles, which react with 2-bromobenzaldehyde to form the corresponding chalcones; these are readily reduced to dihydrochalcones, which are in turn acylated to form the enolate esters. The compounds in this sequence have been characterized by IR and 1H and 13C NMR spectroscopy, by mass spectrometry and by elemental analysis. The molecular and supramolecular structures are reported for representative examples, namely (E)-3-(2-bromophenyl)-2-(1-methyl-1H-indole-3-carbonyl)acrylonitrile, C19H13BrN2O, (Ib), (2RS)-2-(2-bromobenzyl)-3-(1-methyl-1H-indol-3-yl)-3-oxopropanenitrile, C19H15BrN2O, (IIb), and (2RS)-3-(1-benzyl-1H-indol-3-yl)-2-(2-bromobenzyl)-3-oxopropanenitrile, C25H19BrN2O, (IIc), the latter two of which crystallize with Z' = 2, and (E)-1-(1-acetyl-1H-indol-3-yl)-3-(2-bromophenyl)-2-cyanoprop-1-en-1-yl acetate, C22H17BrN2O, (III), and (E)-1-(1-benzyl-1H-indol-3-yl)-3-(2-bromophenyl)-2-cyanoprop-1-en-1-yl benzoate, C32H23BrN2O, (IV). The structure of the related chalcone (E)-2-benzoyl-3-(2-bromophenyl)prop-2-enenitrile, (V), has been redetermined at 100 K, where it is monoclinic, as opposed to the triclinic form reported at ambient temperature.

Age, Gender, and Race-Based Coronary Artery Calcium Score Percentiles in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil).

BACKGROUND: Coronary artery calcium (CAC) has been demonstrated to independently predict the risk of cardiovascular events and all-cause mortality, especially among White populations. Although the population distribution of CAC has been determined for several White populations, the distribution in ethnically admixed groups has not been well established. HYPOTHESIS: The CAC distribution, stratified for age, gender and race, is similar to the previously described distribution in the MESA study. METHODS: The Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) is a prospective cohort study designed to investigate subclinical cardiovascular disease in 6 different centers of Brazil. Similar to previous studies, individuals with self-reported coronary or cerebrovascular disease and those treated for diabetes mellitus were excluded from analysis. RESULTS: Percentiles of CAC distribution were estimated with nonparametric techniques. The analysis included 3616 individuals (54% female; mean age, 50 years). As expected, CAC prevalence and burden were steadily higher with increasing age, as well as increased in men and in White individuals. Our results revealed that for a given CAC score, the ELSA-derived CAC percentile would be lower in men compared with the Multi-Ethnic Study of Atherosclerosis (MESA) and would be higher in women compared with MESA. CONCLUSIONS: In our sample of the Brazilian population, we observed significant differences in CAC by sex, age, and race. Adjusted for age and sex, low-risk individuals from the Brazilian population present with significantly lower CAC prevalence and burden compared with other low-risk individuals from other worldwide populations. Using US-derived percentiles in Brazilian individuals may lead to overestimating relative CAC burden in men and underestimating relative CAC burden in women.

Incidencia y caracterización de la miocardiopatía periparto en el Hospital do Prenda / Incidence and characterization of peripartum cardiomyopathy at the Hospital do Prenda

Introducción: La miocardiopatía periparto es una enfermedad rara que aparece en mujeres sanas y se caracteriza por el desarrollo de disfunción ventricular izquierda y síntomas de insuficiencia cardíaca sistólica, en el período entre el último mes de embarazo y los cinco primeros meses del puerperio. Objetivos: Determinar la incidencia, forma de presentación, tratamiento y mortalidad de las pacientes recibidas en el hospital.Método: Estudio prospectivo de 13 pacientes con diagnóstico de miocardiopatía periparto recibidas en el Hospital do Prenda desde julio de 2012 a julio de 2013. Se analizaron variables demográficas, factores de riesgo, historia ginecológica y obstétrica, síntomas y signos de insuficiencia cardíaca, hallazgos ecocardiográficos y tratamientoutilizado. Resultados: La edad media fue 30,8 ± 7,23 años, predominaron las pacientes mayores de 35 años (38,5 por ciento). La mayoría eran multíparas (84,6 por ciento) y con más de tres gestaciones (61,5 por ciento), como principal factor de riesgo se encontró a la enfermedad hipertensiva del embarazo (53,8 por ciento). Once pacientes fueron diagnosticadas durante las primeras semanas del puerperio. La fracción de eyección media fue de 36,8 ± 10 por ciento. Los medicamentos utilizados con mayor frecuencia fueron espironolactona, otros diuréticos y digitálicos. No hubo fallecidos durante el ingreso.Conclusiones: Los síntomas y signos de insuficiencia cardíaca con fracción de eyección disminuida y el uso de digitálicos y diuréticos fueron las características distintivas de estas pacientes, similares a las informadas en los registros internacionales. La incidencia de esta enfermedad es muy baja y no hubo fallecidas en el período estudiado(AU)

Variaciones al test de hodge modificadopara la detección de carbapenemasasen pseudomonas aeruginosa / Variations in the modified hodge test to detect carbapenemase production in pseudomonas aeruginosa

Introducción: la producción de enzimas con actividad hidrolítica frente a carbapenémicos, denominadascarbapenemasas, es uno de los principales mecanismos de resistencia a carbapenémicos en Pseudomonas aeruginosa. El test de Hodge modificado es la prueba fenotípica más empleada para la detección de carbapenemasas; sin embargo, de acuerdo con el CLSI, este método sólo puede emplearse en Enterobacteriáceas ya que presenta limitaciones en Bacilos Gram negativos no fermentadorescomo Pseudomonas aeruginosa. Objetivo: evaluar la eficacia de variaciones del test de Hodge modificado para la detección de carbapenemasas en aislados de Pseudomonas aeruginosa. Materiales y métodos: se evaluó el desempeño del test 3D y tres variaciones del test de Hodge modificado, tomando como prueba de referencia la detección de los genes de las carbapenemasas KPC, VIM, IMP, NDM y OXA-48 mediante reacción en cadena de la polimerasa. Las variaciones consistieron en emplear: a) agar MacConkey en lugar de Mueller Hinton, b) Klebsiella pneumoniae ATCC 700603 como cepa indicadora sensible a carbapenémicos en lugar de Escherichia coli ATCC 29212 y c) las dos condiciones anteriores simultáneamente. Resultados: de los ensayos evaluados, la tercera variación, que empleó tanto agar MacConkey como la cepa indicadora de Klebsiella pneumoniaeATCC 700603, mostró los mejores valores de sensibilidad y especificidad para la detección de carbapenemasas en Pseudomonas aeruginosa (90,0% y 85,7%, respectivamente). Conclusiones: la implementación de las variaciones del test de Hodge modificado podría ser una alternativa económica y de fácil realización para la detección fenotípica de carbapenemasas en Pseudomonas aeruginosa en los laboratorios de Microbiología Clínica.

Introduction: one of the most important mechanisms of carbapenem resistance in Pseudomonas aeruginosa is the production of carbapenem-hydrolyzing enzymes known as carbapenemases. The modified Hodge test is the most frequently used phenotypic screening test for carbapenemases. Nevertheless,CLSI recommends using modified Hodge test only in members of Enterobacteriaceae, sincethe test has demonstrated limitations in other Gram-negative bacilli and non-glucose-fermenters as Pseudomonas aeruginosa. Objective: To evaluate the performance of 3D test and three variations of modified Hodge test to detect carbapenemases in Pseudomonas aeruginosa isolates. Materials and methods: The efficacy of 3D test and three variations in modified Hodge test were evaluated taking polymerase chain reaction for carbapenemases KPC, VIM, IMP, NDM and OXA-48 as the gold standard. Variations consisted in using a) MacConckey agar instead of Mueller Hinton, b) Klebsiellapneumoniae ATCC 700603 as indicator carbapenem-sensitive strain instead of Escherichia coli ATCC 29212 and c) last two conditions simultaneously. Results: Of the variations tested, the third assay using both MacConckey agar and Klebsiella pneumoniae ATCC 700603 showed the best sensitivity and specificity (90.0% and 85.7%, respectively). Conclusions: The implementation of variations in modified Hodge test could be a cheap and easy to perform alternative for phenotypic carbapenemase detection in Pseudomonas aeruginosa in Clinical Microbiology laboratories.

2-[1'-(Benz-yloxy)spiro-[indane-1,2'-pyrrolidine]-5'-yl]aceto-nitrile.

In the title compound, C21H22N2O, the planes of the two six-membered rings make a dihedral angle of 89.51 (7)°. The pyrrolidine ring has a puckering amplitude q 2 = 0.418 (3) and a pseudo-rotation phase angle ϕ2 = -166.8 (5), adopting a twist conformation (T). The other five-membered ring has a puckering amplitude q 2 = 0.247 (2) and a pseudo-rotation phase angle ϕ2 = -173.7 (5), adopting an envelope conformation with the CH2 atom adjacent to the C atom common with the pyrrolidine ring as the flap. In the crystal, mol-ecules are linked via C-H⋯N, enclosing R (2) 2(20) rings, forming chains propagating along [100]. The aceto-nitrile group is disordered over two positions and was refined with a fixed occupancy ratio of 0.56:0.44.

Hepatotoxicity from ingestion of wild mushrooms of the genus Amanita section Phalloideae collected in Mexico City: two case reports.

We present two cases of acute liver injury resulting from consumption of wild mushrooms. The first case was a male who developed acute hepatitis after ingestion of diverse mushrooms including Amanita species. His clinical course was favorable with complete recovery of liver function. The second case was a male who developed acute liver failure (ALF) after ingestion of Amanita bisporigera. He required MARS therapy as a bridge to liver transplantation but transplantation was not performed because he succumbed to multiorgan failure. There are few trials demonstrating the efficacy of the different treatments for mushroom poisoning. These cases demonstrate that the consumption of wild mushrooms without proper knowledge of toxic species represents a serious and under recognized health problem.