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Herein we report for the first time the diastereoselective synthesis of (2R,3aR,7aS)- and (2S,3aS,7aR)-octahydroindole-2-phosphonic acid (OicP trans-fused stereoisomers) from diethyl (R)- and (S)-phosphopyroglutamate derivative. The key steps of this procedure are the ruthenium tetroxide oxidation of enantiomerically pure diethyl (R)- and (S)-phosphoprolinate obtained through Katritzky's benzotriazole-oxazolidine methodology, a highly diastereoselective successive double 4,5-diallylation of diethyl (R)- and (S)-phosphopyroglutamate with allyl bromide and allyltrimethylsilane with a trans-addition mode, and a ring-closing metathesis with Grubbs' first-generation ruthenium catalyst.

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Among the biological targets extensively investigated to improve inflammation and chronic inflammatory conditions, cyclooxygenase enzymes (COXs) occupy a prominent position. The inhibition of these enzymes, essential for mitigating inflammatory processes, is chiefly achieved through Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). In this work, we introduce a novel method-based on computational molecular docking-that could aid in the structure-based design of new compounds or the description of the anti-inflammatory activity of already-tested compounds. For this, we used eight crystal complexes (four COX-1 and COX-2 each), and each pair had a specific NSAID: Celecoxib, Meloxicam, Ibuprofen, and Indomethacin. This selection was based on the ligand selectivity towards COX-1 or COX-2 and their binding mode. An interaction profile of each NSAID was compiled to detect the residues that are key for their binding mode, highlighting the interaction made by the Me group. Furthermore, we rigorously validated our models based on structural accuracy (RMSD < 1) and (R2 > 70) using eight NSAIDs and thirteen compounds with IC50 values for each enzyme. Therefore, this model can be used for the binding mode prediction of small and structurally rigid compounds that work as COX inhibitors or the prediction of new compounds that are designed by means of a structure-based approach.

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An expedient synthetic entry to cis-4-hydroxyphosphonic and cis-4-hydroxyphosphinic analogs of cis-4-hydroxypipecolic acid is presented in this paper. The main feature of this methodology is the highly regioselective addition of silyl phosphites or phosphonites to cyclic 1-benzyloxycarbonyl enaminones. Interestingly, the hydride reduction of the resulting 2-phospho-4-oxopiperidine proceeds with high diastereofacial preference using NaBH4. In the last step, the cleavage of N-Cbz group under hydrogenolysis followed by the hydrolysis of the phosphonate or phosphinate functionalities, led to the target cis-4-hydroxyphosphonic and cis-4-hydroxyphosphinic acids, respectively.

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Chitinases represent an alternative therapeutic target for opportunistic invasive mycosis since they are necessary for fungal cell wall remodeling. This study presents the design of new chitinase inhibitors from a known hydrolysis intermediate. Firstly, a bioinformatic analysis of Aspergillus fumigatus chitinase B1 (AfChiB1) and chitotriosidase (CHIT1) by length and conservation was done to obtain consensus sequences, and molecular homology models of fungi and human chitinases were built to determine their structural differences. We explored the octahydroisoindolone scaffold as a potential new antifungal series by means of its structural and electronic features. Therefore, we evaluated several synthesis-safe octahydroisoindolone derivatives by molecular docking and evaluated their AfChiB1 interaction profile. Additionally, compounds with the best interaction profile (1-5) were docked within the CHIT1 catalytic site to evaluate their selectivity over AfChiB1. Furthermore, we considered the interaction energy (MolDock score) and a lipophilic parameter (aLogP) for the selection of the best candidates. Based on these descriptors, we constructed a mathematical model for the IC50 prediction of our candidates (60-200 µM), using experimental known inhibitors of AfChiB1. As a final step, ADME characteristics were obtained for all the candidates, showing that 5 is our best designed hit, which possesses the best pharmacodynamic and pharmacokinetic character.

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Resumen Introducción. El tumor fibroso solitario de pleura (TFSP) es una neoplasia poco frecuente, con aproximadamente 1.000 casos reportados en la literatura mundial. La aproximación diagnóstica inicial se realiza con estudios imagenológicos. Métodos. De forma retrospectiva, se recopilaron cuatro casos de pacientes con TFSP gigante operados en nuestra institución. Se describen las características sociodemográficas, clínicas, imagenológicas, macroscópicas y microscópicas de cada caso. Resultados. Todos los pacientes de la serie cursaron con manifestaciones clínicas, con un promedio de 23,75 meses de evolución. El 50% de los tumores se localizaron en la cavidad pleural derecha y el 50% en la izquierda. En tomografía computarizada (TC) de tórax, los cuatro casos se presentaron como una masa sólida, de densidad heterogénea, con diámetros mayores entre 17 y 22 cm y contornos variables (lisos en tres casos y lobulados en un paciente). Se observaron calcificaciones intratumorales en dos casos y derrame pleural en tres pacientes. En cirugía, todas las masas presentaron pedículos. El análisis histológico e inmuno-químico confirmó la naturaleza benigna de tres casos y malignidad en una de las neoplasias. Conclusiones. Los TFSP generalmente son benignos y de buen pronóstico. Sin embargo, entre 10 y 20% de esos tumores son malignos. Las imágenes diagnósticas pueden sugerir el diagnóstico de TFSP, pero la confirmación de la naturaleza de la lesión debe realizarse con el análisis histopatológico de toda la pieza quirúrgica.

Abstract Introduction. Solitary fibrous tumor of the pleura (SFTP) is a rare neoplasm, with ~1.000 cases reported in the worldwide literature. The initial diagnostic approach is performed by imaging studies. Methods. Retrospectively, we collected four cases of patients with giant SFTP operated in our institution. The sociodemographic, clinical, imaging, macroscopic, and microscopic characteristics of each case are described. Results. All the patients in the series had clinical manifestations, with an average of 23.75 months of evolution. 50% of the tumors were located in the right pleural cavity and 50% in the left. In chest computed tomography (CT), the four cases presented as a solid mass, of heterogeneous density, with greater diameters between 17 and 22 cm, and variable contours (smooth in three cases and lobulated in one patient). Intratumoral calcifications were observed in two cases and pleural effusion in three patients. In surgery, all masses presented pedicles. The histological and immunochemical analysis confirmed the benign nature of three cases and malignancy in one of them. Conclusions. SFTPs are usually benign and have a good prognosis. However, between 10 and 20% of these tumors are malignant. Diagnostic images may suggest the diagnosis of SFTP, but confirmation of the nature of the lesion should be made with the histopathological analysis of the entire surgical specimen.

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Kinetically controlled cyclocondensation of stereoisomeric and ring-chain tautomeric mixture of (±)-hydroxylactone 1 and 0.5 equiv of (R)-phenylglycinol provided tricyclic oxazoloisoindolone lactam (3R,5aS,9aR,9bS)-2a, a versatile intermediate for further stereocontrolled transformations to access enantiopure cis-fused octahydroisoindolones. An extension of this methodology was successfully applied to the synthesis of the 5,6-dihydroxy derivative (3aR,5R,6S,7aS)-17.

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Two new strategies for the efficient synthesis of racemic 1,2,3,4-tetrahydroisoquinoline-3-phosphonic acid (TicP) (±)-2 have been developed. The first strategy involves the electron-transfer reduction of the easily obtained α,ß-dehydro phosphonophenylalanine followed by a Pictet-Spengler cyclization. The second strategy involves a radical decarboxylation-phosphorylation reaction on 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic). In both strategies, the highly electrophilic N-acyliminium ion is formed as a key intermediate, and the target compound is obtained in good yield using mild reaction conditions and readily available starting materials, complementing existing methodologies and contributing to the easy accessibility of (±)-2 for further research.

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The montages in clinical EEG recordings in neonates, infants, and children follow some basic principles of adolescent or adult EEG recordings; however, special considerations are needed to obtain optimal diagnostic yield in pediatric patients. The aim of this review is to summarize the pediatric montages recommended in clinical practice in the standard clinical neurophysiology laboratory and in special situations.

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The reaction of the title lactams with triethyl phosphite prompted by phosphoryl chloride provided six-membered ring heterocyclic phosphonates or bisphosphonates. These novel scaffolds might be of interest as building blocks in medicinal chemistry. The course of the reaction was dependent on the structure of the used substrate. Thus, morpholin-3-one and thiomorpholin-3-one readily provided the corresponding 1,1-bisphosphonates (compounds 1, 2, 7, 14 and 16), whereas the protection of their nitrogen atom resulted in the formation of dehydrophosphonates (compounds 5, 6, and 8). Piperazin-2-one reacted differently yielding mixture of cis- and trans- piperazine-2,3-diyl-bisphosphonates (compounds 10 and 11). Since cytosine could be considered as an analogue of piperin-2-one, its ditosyl derivative 18 was used as a substrate affording compound 19 being a product of phosphite addition to double bond. In dependence of their structures, hydrolysis of the obtained diethyl phosphonates resulted either in corresponding cyclic phosphonic acids or in the degradation of carbon-to-phosphorus bond.

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Resumen Introducción : el tumor fibroso solitario de pleura (TFSP) es una patología poco frecuente, corresponde a menos del 5 % de los tumores primarios de pleura, siendo aún más raros los tumores mayores de 15 cm y aquellos en pacientes menores de 35 años, ya que el pico de incidencia es entre los 60 a 70 años con un solo caso reportado en Colombia. Presentación del caso : paciente femenina de 33 años, sin exposición a asbesto o cigarrillo. Consultó por cuadro de disnea de moderados esfuerzos y dolor dorsal derecho. La tomografía axial computarizada (TAC) contrastada de tórax evidenció una gran masa sólida de contornos lobulados que comprometía el 70 % del hemitórax derecho de origen extrapulmonar y que comprimía la aurícula derecha, la inmunohistoquímica de la biopsia percutánea clasificó la lesión como tumor fibroso solitario. Fue llevada a toracotomía posterolateral derecha extendida, donde se encontró un tumor dependiente de la pleura parietal derecha resecado en su totalidad. Histopatología e inmunohistoquímica del producto de resección quirúrgica, compatibles con tumor fibroso solitario de pleura, tamaño 30 x 23 x 16 cm sin características de malignidad. La evolución posoperatoria fue satisfactoria, con un egreso hospitalario temprano. Discusión : en una paciente joven, el TFSP gigante es inusual, posterior a su diagnóstico, y a pesar de tener algunas características que sugerían malignidad: tamaño y origen en la pleura parietal, la resección quirúrgica fue el tratamiento indicado para este tumor, con posterior confirmación histopatológica compatible con tumor benigno.

Abstract Introduction : The solitary fibrous tumor of the pleura (SFTP) is an uncommon pathology. It corresponds to less than 5 % of the primary tumors of the pleura. Even much rare is to find one solitary fibrous tumor, of more than 15 cm in patients younger than 35 years since the incidence peak is between 60 to 70 years. There has been only one case reported in Colombia. Case presentation : The subject of study was a 33-year-old female patient, no exposure to asbestos or cigarette. The chief complaints of the patient were mild dyspnea and right dorsal pain. Thoracic contrast-enhanced computerized tomography showed a large solid mass of lobulated contours that compromised 70 % of the right hemithorax, of extrapulmonary origin compressing the right atrium. Immunohistochemistry of the percutaneous biopsy demonstrated a solitary fibrous tumor. The patient underwent an extended right posterolateral thoracotomy. We found and completely resected a tumor hanging on the right parietal pleura. Histopathology and immunohistochemistry of the product of the surgical resection were compatible with a solitary fibrous tumor of the pleura, 30 x 23 x 16cm in size, and no malignancy. The evolution after surgery was satisfactory with an early hospital discharge. Discussion : In a young patient, a giant TFSP is unusual. After diagnosis and despite having some characteristics that suggested malignancy: its size and origin in the parietal pleura, surgical resection was the appropriate procedure for this tumor, with subsequent histopathological confirmation compatible with a benign tumor.

Resumo Introdução : o tumor fibroso solitário de pleura (TFSP) é uma patologia pouco frequente, corresponde a menos do 5 % dos tumores primários de pleura, sendo ainda mais estranhos os tumores maiores de 15 cm e aqueles em pacientes menores de 35 anos, pois o pico de incidência é entre os 60 a 70 anos com um só caso reportado na Colômbia. Apresentação de caso : paciente feminina de 33 anos, sem exposição a asbesto ou cigarro. Consultou por quadro de dispneia de moderados esforços e dor dorsal direita. A tomografia axial computadorizada (TAC) contrastada de tórax evidenciou uma grande massa sólida de contornos lobulados que comprometia o 70 % do hemitórax direito de origem extrapulmonar e que comprimia a aurícula direita, imuno-histoquímica da biopsia percutânea classificou a lesão como tumor fibroso solitário. Foi levada à toracotomia posterolateral direita estendida, encontrando um tumor dependente da pleura parietal direita ressecado em sua totalidade. Histopatologia e imuno-histoquímica do produto de ressecção cirúrgica, compatíveis com tumor fibroso solitário de pleura, tamanho 30 x 23 x 16cm sem características de malignidade. A evolução pós-cirúrgica foi satisfatória, conseguindo um egresso hospitalar precoce. Discussão : em uma paciente jovem, o TFSP gigante é inusual, posterior a seu diagnóstico e apesar de ter algumas características que sugeriam malignidade; tamanho e origem na pleura parietal, a ressecção cirúrgica foi o tratamento indicado para este tumor, com posterior confirmação hispatológica compatível com tumor benigno.

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In this paper, we report the synthesis of a new series of α-aminophosphonates derivatives based in an efficient three-component reaction. All compounds prepared showed significant anti-inflammatory activity, being the compounds 1a, 1c, 1d, 1f, 2b and 2c the most promising ones, in terms of maximal efficacy (over 95%), potency (ED50 range between 0.7 and 10.1 mg/ear) and relative potency (range from 0.04 to 0.67). Compounds 1a, 1c, 1d and 1f significantly decrease the number of neutrophils (range from 46.7 to 63.0%) and monocytes (18.9-34.1%) in blood samples from the orbital sinus. Additionally, QSAR model revealed that the spherical molecular shape and the location of the HOMO on the phenyl ring improves the anti-inflammatory activity of the compounds. The values of R2, Q2, s and F statistical parameters and the QUIK, asymptotic Q2 and Overfitting rules validate the descriptive and predictive ability of the QSAR model. Altogether these results suggest that these new α-aminophosphonates are potential agents for the treatment of inflammation.

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INTRODUCTION: Intraoperative neurophysiological monitoring (IONM) is a procedure that uses neurophysiological techniques in order to evaluate the motor and sensitive systems during surgeries that endanger the nervous system. METHOD: The approach, scope, target population, and clinical questions to be answered were defined. A systematic search of the evidence was conducted step by step; during the first stage, clinical practice guidelines were collected, during the second stage systematic reviews were obtained, and during the third stage, clinical trials and observational studies were procured. The MeSH nomenclature and free related terminology were used, with no language restrictions and a 5-10 years frame. The quality of the evidence was graded using the CEPD and SIGN scales. RESULTS: Obtained using the search algorrhythms of 892 documents. Fifty-eight were chosen to be included in the qualitative synthesis. A meta-analysis was not possible due to the heterogeneity of the studies. CONCLUSIONS: Eighteen recommendations were issued and will support the adequate use of the IONM.

INTRODUCCIÓN: El monitoreo neurofisiológico intraoperatorio (MNIO) es un procedimiento que emplea técnicas neurofisiológicas con la finalidad de evaluar los sistemas motor y sensitivo durante cirugías que ponen en riesgo al sistema nervioso. MÉTODO: Se definieron el enfoque, los alcances, la población diana y las preguntas clínicas por resolver. Se realizó una búsqueda sistematizada de la evidencia por etapas. En la primera, se buscaron guías de práctica clínica; en la segunda, revisiones sistemáticas; y en la tercera, ensayos clínicos y estudios observacionales. Se utilizaron los términos MeSH y libres correspondientes, sin restricciones de lenguaje y con una temporalidad de 5 a 10 años. Se graduó la calidad de la evidencia utilizando las escalas CEPD y SIGN. RESULTADOS: Mediante los algoritmos de búsqueda se obtuvieron 892 documentos, y se seleccionaron 58 para la inclusión de la síntesis cualitativa. Debido a la heterogeneidad entre los estudios, no fue posible realizar metaanálisis. CONCLUSIONES: Se emitieron 18 recomendaciones, las cuales servirán como apoyo para la adecuada utilización del MNIO.

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The synthesis of six α,ß,-unsaturated amides and six 2,4-disubstituted oxazolines derivatives and their evaluation against two Mycobacterium tuberculosis strains (sensitive H37Rv and a resistant clinical isolate) is reported. 2,4-Disubstituted oxazolines (S)-3b,d,e were the most active in the sensitive strain with a MIC of 14.2, 13.6 and 10.8µM, respectively, and the compounds (S)-3d,f were the most active against resistant strain with a MIC of 6.8 and 7.4µM. The ex-vivo evaluation of hepatotoxicity on precision-cut rat liver slices was also tested for the α,ß-unsaturated amides (S)-2b and (S)-2d,f and for the oxazolines (S)-3b and (S)-3d,f at different concentrations (5, 15 and 30µg/mL). The results indicate that these compounds possess promising antimycobacterial activity and at the same time are not hepatotoxic. These findings open the possibility for development of new drugs against tuberculosis.

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α-Amino-C-phosphinic acids and derivatives are an important group of compounds of synthetic and medicinal interest and particular attention has been dedicated to their stereoselective synthesis in recent years. Among these, phosphinic pseudopeptides have acquired pharmacological importance in influencing physiologic and pathologic processes, primarily acting as inhibitors for proteolytic enzymes where molecular stereochemistry has proven to be critical. This review summarizes the latest developments in the asymmetric synthesis of acyclic and phosphacyclic α-amino-C-phosphinic acids and derivatives, following in the first case an order according to the strategy used, whereas for cyclic compounds the nitrogen embedding in the heterocyclic core is considered. In addition selected examples of pharmacological implications of title compounds are also disclosed.

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We report here a practical and efficient synthesis of α-aminophosphonic acid incorporated into 1,2,3,4-tetrahydroquinoline and 1,2,3,4-tetrahydroisoquinoline heterocycles, which could be considered to be conformationally constrained analogues of pipecolic acid. The principal contribution of this synthesis is the introduction of the phosphonate group in the N-acyliminium ion intermediates, obtained from activation of the quinoline and isoquinoline heterocycles or from the appropriate δ-lactam with benzyl chloroformate. Finally, the hydrolysis of phosphonate moiety with simultaneous cleavage of the carbamate afforded the target compounds.

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Practical and convenient method for the synthesis of novel phosphonopeptides 8a-h and 10a-f incorporating the quaternary α-aminophosphonate 6 is reported. The target compounds were prepared in moderate to good yield based on the preparation of the quaternary α-aminophosphonate 6 followed by the formation of the α-bromoamide 7 and subsequent nucleophilic substitution reaction with several amines or by peptide bond formation with several amino acids and with the quaternary α-aminophosphonate 6, using isobutyl chloroformate as activating agent under racemization-free condition.

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An efficient synthesis of enantiomerically-pure ß-aryl-γ-lactams is described. The principal feature of this synthesis is the practical resolution of ß-aryl-γ-lactams with (S)-Naproxen. The procedure is based on the Michael addition of nitromethane to benzylidenemalonates, which was easily obtained, followed by the reduction of the γ-nitroester in the presence of Raney nickel and the subsequent saponification/decarboxylation reaction. The utility of this methodology was highlighted by the preparation of enantiomerically-pure (R)- and (S)-Baclofen hydrochloride.

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Synthesis and structural characterization of 1,4,2-oxazaphosphepines is described. The 1,4,2-oxazaphosphepines were obtained from reaction of chiral 1,3-benzoxazines with dichlorophenylphosphine or triethyl phosphite. The configuration of some of these compounds was stablished by X-ray analysis.

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A regioselective synthesis has been developed for the preparation of a series of N,N'-disubstituted 4,4'-carbonylbis(carbamoylbenzoic) acids and N,N'-disubstituted bis(carbamoyl) terephthalic acids by treatment of 3,3',4,4'-benzophenonetetracarboxylic dianhydride (1) and 1,2,4,5-benzenetetracarboxylic dianhydride (2) with arylalkyl primary amines (A-N). The carbamoylcarboxylic acid derivatives were synthesized with good yield and high purity. The specific reaction conditions were established to obtain carbamoyl and carboxylic acid functionalities over the thermodynamically most favored imide group. Products derived from both anhydrides 1 and 2 were isolated as pure regioisomeric compounds under innovative experimental conditions. The chemo- and regioselectivity of products derived from dianhydrides were determined by NMR spectroscopy and confirmed by density functional theory (DFT). All products were characterized by NMR, FTIR, and MS.

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We describe a protocol developed for the preparation of ß-enaminoketones derived from 1,3-cyclohexanediones, and their subsequent reduction by sodium in THF-isopropyl alcohol to afford cis- and trans-3-aminocyclohexanols.

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