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1.
J Am Chem Soc ; 142(33): 14045-14051, 2020 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-32608977

RESUMO

Ammonium salts are used as phase-transfer catalysts for fluorination with alkali metal fluorides. We now demonstrate that these organic salts, specifically azetidinium triflates, are suitable substrates for enantioselective ring opening with CsF and a chiral bis-urea catalyst. This process, which highlights the ability of hydrogen bonding phase-transfer catalysts to couple two ionic reactants, affords enantioenriched γ-fluoroamines in high yields. Mechanistic studies underline the role of the catalyst for phase-transfer, and computed transition state structures account for the enantioconvergence observed for mixtures of achiral azetidinium diastereomers. The N-substituents in the electrophile influence the reactivity, but the configuration at nitrogen is unimportant for the enantioselectivity.

2.
Angew Chem Int Ed Engl ; 57(28): 8473-8477, 2018 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-29566297

RESUMO

The merging of photoredox and transition-metal catalysis has become one of the most attractive approaches for carbon-carbon bond formation. Such reactions require the use of two organo-transition-metal species, one of which acts as a photosensitizer and the other one as a cross-coupling catalyst. We report herein an exogenous-photosensitizer-free photocatalytic process for the formation of carbon-carbon bonds by direct acceleration of the well-known nickel-catalyzed Negishi cross-coupling that is based on the use of two naturally abundant metals. This finding will open new avenues in cross-coupling chemistry that involve the direct visible-light absorption of organometallic catalytic complexes.

3.
JACS Au ; 4(7): 2585-2595, 2024 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-39055158

RESUMO

Light-mediated reactions have emerged as an indispensable tool in organic synthesis and drug discovery, enabling novel transformations and providing access to previously unexplored chemical space. Despite their widespread application in both academic and industrial research, the utilization of light as an energy source still encounters challenges regarding reproducibility and data robustness. Herein we present a comprehensive head-to-head comparison of commercially available batch photoreactors, alongside the introduction of the use of batch and flow photoreactors in parallel synthesis. Hence, we aim to establish a reliable and consistent platform for light-mediated reactions in high-throughput mode. Herein, we showcase the identification of several platforms aligning with the rigorous demands for efficient and robust high-throughput experimentation screenings and library synthesis.

4.
J Med Chem ; 66(1): 716-732, 2023 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-36520521

RESUMO

Herein, we report an end-to-end process including synthesis, work-up, purification, and post-purification with minimal human intervention using Negishi coupling as a key transformation to increase Fsp3 in bioactive molecules. The main advantages of this protocol are twofold. First, the automated sequential generation of organozinc reagents from readily available alkyl halides offers a large diversity of alkyl groups to functionalize (hetero)aryl halide scaffolds via Pd-catalyzed Negishi coupling in continuous flow. Second, a fully automated liquid-liquid extraction has been developed and successfully applied for unattended operations. The workflow was completed with mass-triggered preparative high-performance liquid chromatography HPLC, providing an efficient production line of compounds with enriched sp3 character and better drug-like properties. The modular nature allows a smooth adaptation to a wide variety of synthetic methods and protocols and makes it applicable to any medchem laboratory.


Assuntos
Cromatografia Líquida de Alta Pressão , Humanos , Indicadores e Reagentes
5.
J Pharm Biomed Anal ; 178: 112908, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31610393

RESUMO

The need of a continuous productivity increases in medicinal chemistry laboratories of the pharmaceutical industry motivated the development, over the years, of new software solutions to enable Open-Access in many analytical techniques such as NMR or LC, among others, to characterize and assess the purity of new molecules. These approaches have been widely spread in LC with low resolution MS systems, but similar automated platforms have been rather less explored with high resolution MS. In this work, an improved Automated Open-Access methodology on an UHPLC with DAD coupled to ESI and quadrupole time-of-flight MS system is described. Detailed reports from standard UHPLC-MS runs containing chromatograms and different spectra (MS with different fragmentation) are automatically sent to the chemists. High resolution MS data is typically achieved within ± 1 mDa mass accuracy regardless of sample concentration. Upon training, chemists log-in samples into the system by selecting appropriate methods, being able to interpret the results by themselves in 95% of the cases. The instrument is working unattended, except for a limited number of samples (5%) which require more complex experiments. To the best of our knowledge, this is the first time a completely automated Open-Access LC-HRMS approach has been implemented for medicinal chemists of a pharmaceutical industry.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Descoberta de Drogas/métodos , Espectrometria de Massas por Ionização por Electrospray/métodos , Química Farmacêutica/métodos , Indústria Farmacêutica/métodos
6.
ACS Chem Neurosci ; 10(3): 1043-1054, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30216043

RESUMO

The metabotropic glutamate 7 (mGlu7) receptor belongs to the group III of mGlu receptors. Since the mGlu7 receptor can control excitatory neurotransmission in the hippocampus and cortex, modulation of the receptor may have therapeutic benefit in several CNS diseases. However, mGlu7 remains relatively unexplored among the eight known mGlu receptors partly because of the limited availability of tool compounds to interrogate its potential therapeutic utility. Here we report the discovery of a new class of mGlu7 allosteric agonists. Hits originating from virtual screening were followed up with further analogue searching and screening, leading to a novel series of mGlu7 allosteric agonists. Guided by docking into a structural model of the mGlu7 receptor the initial hit 5 was successfully optimized to analogues with comparable potencies and more attractive drug-like attributes than AMN082.


Assuntos
Agonistas de Aminoácidos Excitatórios/química , Agonistas de Aminoácidos Excitatórios/farmacologia , Simulação de Acoplamento Molecular/métodos , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/química , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/fisiologia , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ratos , Receptores de Glutamato Metabotrópico/metabolismo
7.
Comb Chem High Throughput Screen ; 10(3): 163-9, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17346115

RESUMO

The heating of different parallel arrays in domestic ovens offers the possibility to perform multiple reactions in one irradiation experiment, blending the advantages of microwave heating technology and parallel chemistry. However, they are usually performed without an appropriate temperature control; thus, reproducibility becomes a major issue limiting the application of such reactions. This is exemplified when working at a different scales or using different instruments. For the first time a typical solvent-free reaction described in a domestic oven has been reproduced in monomode reactor, scaled up in a controlled multimode oven and reproduced in parallel, 24 reactions were carried out in a well plate. Parallel reactions were performed in a Weflon multiwell plate to assure identical conditions for each individual reaction. As many reactions under microwave irradiation have been performed in solvent-free conditions, this result opens new possibilities in reproducibility, scalability and combinatorial chemistry and permits to take advantage of many synthetic procedures described in domestic ovens.


Assuntos
Química Orgânica/métodos , Micro-Ondas , Química Orgânica/instrumentação , Técnicas de Química Combinatória , Desenho de Equipamento , Temperatura Alta
8.
J Med Chem ; 60(4): 1272-1291, 2017 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-28106992

RESUMO

A mini-HTS on 4000 compounds selected using 2D fragment-based similarity and 3D pharmacophoric and shape similarity to known selective tau aggregate binders identified N-(6-methylpyridin-2-yl)quinolin-2-amine 10 as a novel potent binder to human AD aggregated tau with modest selectivity versus aggregated ß-amyloid (Aß). Initial medicinal chemistry efforts identified key elements for potency and selectivity, as well as suitable positions for radiofluorination, leading to a first generation of fluoroalkyl-substituted quinoline tau binding ligands with suboptimal physicochemical properties. Further optimization toward a more optimal pharmacokinetic profile led to the discovery of 1,5-naphthyridine 75, a potent and selective tau aggregate binder with potential as a tau PET tracer.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/análise , Encéfalo/diagnóstico por imagem , Naftiridinas/química , Tomografia por Emissão de Pósitrons/métodos , Agregação Patológica de Proteínas/diagnóstico por imagem , Proteínas tau/análise , Aminação , Animais , Haplorrinos , Humanos , Camundongos , Naftiridinas/farmacocinética , Ratos
9.
Int Surg ; 91(2): 68-71, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16774174

RESUMO

An immunological deficit is often associated with cancer processes. Because cortisol has an important immunosuppressive activity and it is strictly involved in stress responses, we examined its serum levels in colorectal cancer patients and its relationships with peripheral lymphocyte counts. Cortisol circadian rhythm and total and CD4+ lymphocytes were determined in 40 patients. The rate of patients with an altered cortisol circadian rhythm was 28%, and it was significantly more frequent in patients with nodal involvement (P < 0.005) and with metastatic spread (P < 0.005). Patient ratio with total lymphocytes assessment decrease was 30%. There was no correlation between lymphocytopenia and alteration of cortisol circadian rhythm. Data suggest a significant adrenal glands rhythm modification during cancer processes, associated with poor prognostic factors. Cortisol levels and lymphocytopenia seem not to be related. The origins of these alterations are unknown. They may favor or result from cancer spread.


Assuntos
Neoplasias Colorretais/imunologia , Neoplasias Colorretais/fisiopatologia , Hidrocortisona/sangue , Contagem de Linfócitos , Glândulas Suprarrenais/fisiopatologia , Idoso , Contagem de Linfócito CD4 , Ritmo Circadiano , Feminino , Humanos , Masculino , Metástase Neoplásica
10.
Rev. argent. cir ; 113(1): 101-110, abr. 2021. graf
Artigo em Espanhol | LILACS, BINACIS | ID: biblio-1288179

RESUMO

RESUMEN Antecedentes: el aprendizaje de tareas complejas en cirugía requiere la coordinación e integración de habilidades técnicas y no técnicas que impactan en el rendimiento de los equipos de trabajo. Objetivo: presentar la evaluación de una estrategia educativa basada en simulación para el entrena miento de una habilidad compleja en cirugía, desde la perspectiva de los participantes. Material y métodos: en 2019 se desarrolló un curso de 20 horas (6 horas virtuales y 14 presenciales). Participaron 10 profesionales de la salud. Como estrategia se diseñó la integración de actividades de resolución de casos, role playing, práctica con simuladores sintéticos y virtuales y simulación de alta fidelidad. Al finalizar se realizó un cuestionario sobre percepción de aprendizaje y cambios actitudi nales. Resultados: el 50% tuvo percepción de mejora de sus habilidades y conocimientos al finalizar el cur so. Sin embargo, cuando se preguntó por el impacto del curso sobre su actividad profesional, el 80% respondió niveles superiores al aprendizaje percibido. El 100% se refirió a la necesidad de mejorar habilidades no técnicas. Todos calificaron la experiencia como positiva o muy positiva, y con ganas de repetirla. Conclusión: la perspectiva de quienes participaron de este programa formativo da cuenta de la alta aceptación del método. El hacer conscientes las habilidades no técnicas durante la etapa de reflexión sugiere cambios no solo actitudinales sino sobre la autopercepción de eficacia. Creemos que la meto dología de entrenamiento de equipos basado en simulación tiene potencialidad de mejorar el rendi miento global y futuros estudios deberían estar orientados a ello.


ABSTRACT Background: Learning complex tasks in surgical requires the coordination and integration of technical and non-technical skills have an impact on the performance of work teams. Objective: The aim of this study is to report the results of a simulation-based educational strategy for training in complex surgical skills considering the participants' perceptions. Material and methods: In 2019, 10 healthcare professionals participated in a 20-hour course divided in 6 hours of online training and 14 hours of onsite training. The strategy designed included the inte gration of case resolution activities, role-playing, practice with synthetic and virtual simulators and high-fidelity simulation. At the end of the course, a questionnaire was administered to explore partici pants' perceptions on what they had learned and on their attitude changes. Results: Fifty percent of the participants perceived their skills and knowledge improved at the end of the course compared with their perception at the beginning of the course while 80% perceived the impact of the course on their professional activity was good or excellent. All the participants agreed with the need for improving non-technical skills. The experience was rated as positive or very positive by all participants, who were eager to repeat it. Conclusion: The participants' perceptions of this educational program demonstrates that this method is highly accepted. Raising awareness of non-technical skills during the reflection stage suggests the need for changes in attitude and in self-perception of efficacy. We believe that simulation-based tra ining offers the possibility of improving the overall performance of the surgical team. Future studies should focus on this goal.


Assuntos
Humanos , Masculino , Feminino , Cirurgia Geral
11.
J Med Chem ; 58(2): 978-93, 2015 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-25495129

RESUMO

We report the continuation of a focused medicinal chemistry program aimed to further optimize a series of imidazo[1,2-a]pyrazines as a novel class of potent and selective phosphodiesterase 10A (PDE10A) inhibitors. In vitro and in vivo pharmacokinetic and pharmacodynamic evaluation allowed the selection of compound 25a for its assessment in preclinical models of psychosis. The evolution of our medicinal chemistry program, structure-activity relationship (SAR) analysis, as well as a detailed pharmacological profile for optimized lead 25a are described.


Assuntos
Inibidores de Fosfodiesterase/síntese química , Diester Fosfórico Hidrolases , Administração Oral , Animais , Disponibilidade Biológica , Modelos Animais de Doenças , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Ratos , Ratos Wistar , Esquizofrenia/tratamento farmacológico , Relação Estrutura-Atividade
12.
Chir Ital ; 55(2): 261-5, 2003.
Artigo em Italiano | MEDLINE | ID: mdl-12744103

RESUMO

We report the case of a patient with von Recklinghausen's disease, who was admitted with a diagnosis of acute abdomen due to small bowel neurofibromatosis. The patient was submitted to an abdominal CT scan that showed a homogeneous round lesion, with a regular margin, probably belonging to the small bowel and with the appearance of a benign lesion that probably caused an intestinal intussusception. The patient was submitted to a surgical procedure that mainly consisted in multiple small bowel resections. The histopathological examination confirmed the benign nature of the lesions. About one third of patients affected by von Recklinghausen's disease present involvement of the bowel, but only 5% of them are symptomatic. The intestinal tumours are usually neurofibromas and are mainly localized in the jejunum. However, there have also been reports of stromal, nervous and endocrine tumours and even other tumours not belonging to these categories, including adenocarcinoma. The overall incidence of intestinal malignancy in patients with von Reckilnghausen's disease is about 10%. The surgical operation, as well as the histopathological and immunochemical examination of the intestinal lesions are of crucial importance for the treatment of the complications of intestinal neurofibromatosis and for the treatment and diagnosis of malignancy.


Assuntos
Abdome Agudo/etiologia , Neoplasias Intestinais/diagnóstico , Neoplasias Intestinais/cirurgia , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/cirurgia , Diagnóstico Diferencial , Feminino , Humanos , Neoplasias Intestinais/complicações , Neoplasias Intestinais/diagnóstico por imagem , Pessoa de Meia-Idade , Neurofibromatose 1/complicações , Neurofibromatose 1/diagnóstico por imagem , Tomografia Computadorizada por Raios X
13.
Comb Chem High Throughput Screen ; 14(2): 109-16, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21143180

RESUMO

Organic reactions performed in the absence of solvent in domestic ovens without appropriate temperature control are generally considered as not reproducible, particularly when different instruments are used. For this reason, reproducibility has historically been one of the major issues associated with Microwave-Assisted Organic Synthesis (MAOS) especially when domestic ovens are involved. The lack of reproducibility limits the general applicability and the scale up of these reactions. In this work several solvent-free reactions previously carried out in domestic ovens have been translated into a single-mode microwave reactor and then scaled up in a multimode oven. The results show that most of these reactions, although not considered as reproducible, can be easily updated and applied in microwave reactors using temperature-controlled conditions. Furthermore, computational calculations can assist to explain and/or predict whether a reaction will be reproducible or not.


Assuntos
Técnicas de Química Combinatória/métodos , Micro-Ondas , Alquilação , Compostos de Anilina/química , Brometos/química , Química Orgânica/métodos , Oxirredução , Piridinas/química , Reprodutibilidade dos Testes , Temperatura , Tioureia/química , Triazóis/química , Ureia/química
14.
J Pediatr Hematol Oncol ; 25(8): 640-3, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12902919

RESUMO

The authors retrospectively reviewed their experience with 14 cases of fetal rhabdomyomatous nephroblastoma (15.6% of all renal tumors seen in the 1984-1998 period), analyzing the diagnostic and treatment approach as well outcome. Mean age at presentation was 27 months; 10 (71%) patients were younger than 36 months (5 of these were less than 12 months) at diagnosis. Three patients had bilateral tumors. One case was extrarenal. Nine patients received preoperative chemotherapy after fine-needle aspiration biopsy. The response was null in five children and mild in three; in the remaining one the tumor increased in size. The only patient showing greater than 50% tumor shrinkage was the one treated with radiotherapy. Postoperative treatment according to staging followed the SIOP protocol. In the follow-up (mean 59.5 months) of 12 patients, 6 were in stages 1-2: 4 are alive and free of disease and 2 died (one due to intractable local recurrence and the other in complete clinical remission). All six patients presenting in advanced stages died (four due to disease progression and two due to complications while in complete clinical remission). Patients with fetal rhabdomyomatous nephroblastoma presenting with distant metastatic disease and high stage have unfavorable outcomes, confirming data from the literature indicating that chemotherapy is not as effective as in other variants of nephroblastoma. New protocols are needed to overcome this situation, for which surgery appears the only truly effective option.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Rabdomioma/tratamento farmacológico , Rabdomioma/patologia , Tumor de Wilms/tratamento farmacológico , Tumor de Wilms/patologia , Idade de Início , Pré-Escolar , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Lactente , Masculino , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
16.
Ludovica pediátr ; 10(2): 50-61, mar. 2008. tab, graf
Artigo em Espanhol | LILACS | ID: lil-575292

RESUMO

El cáncer es una enfermedad de rara ocurrencia en pediatría y adolescencia (10-19 años). Casi el 70 % de las neoplasias ocurren en pacientes menores de 5 años. Presentamos nuestra experiencia sobre 224 pacientes adolescentes con una enfermedad neoplásica no hematológica. El 61 % correspondieron al sexo masculino. La incidencia relativa de las neoplasias fue: tumores del sistema nerviosos central 30,5 %, sarcomas de partes blandas 22,7 %, tumores de hueso 18,1 %, tumores germinales 11,8 %, carcinomas 6,3 %, nefroblastoma 2,9 % y neuroblastoma 0,9 %.Comparando dos periodos diferentes (1984-89 y 1990-99) la sobrevida libre de enfermedad (SLE) a 48 meses fue de 39,4 % (45/114) y 81,8 % (90/110), respectivamente mientras que 49 % y 35,5 % presentaron secuelas, respectivamente. La adaptación social posterior a la curación orgánica de la enfermedad mostró que solo 4/135 pacientes (2,9 %) están en la Universidad; el grupo mas numerosos correspondió a aquellos con instrucción primaria incompleta (42,2 % versus 33 %). El 37 % y 53,3 % respectivamente, trabajan (intermitentemente) y el 13,3 % y el 15,5 % han formado pareja. De estos últimos 20 pacientes, el 35 % tiene 10 hijos; 6 son mujeres y 3 tenían tumores pelvianos, dos de ellas de ovario (tumores germinales).


Assuntos
Adolescente , Adolescente , Carcinoma , Neoplasias , Neuroblastoma , Tumor de Wilms , Neoplasias Ósseas , Neoplasias Embrionárias de Células Germinativas
17.
Arch. argent. pediatr ; 84(4): 215-8, 1986. ilus, tab
Artigo em Espanhol | LILACS | ID: lil-45707

RESUMO

Se presenta el resultado del estudio de 66 tumores pediátricos por punción-aspiración con aguja fina. Cuarenta casos tuvieron localización abdominal, el resto estuvo en el tórax, cabeza, cuello y otros lugares. El 42% de los casos correspondieron a tumores renales y neroblastomas. En el 100% de los casos el método fue sensible para determinar las características del tumor (benigno versus maligno; 49 malignos, 17 banigos). La especificidad diagnóstica fue de 93,8% (46/49) en las neoplasias malignas (diagnóstico del tipo histológico por el material de punción-aspiración). No hubo complicaciones


Assuntos
Humanos , Biópsia por Agulha/métodos , Neoplasias/diagnóstico
18.
Acta psiquiátr. psicol. Am. Lat ; 34(2): 149-55, jun. 1988.
Artigo em Espanhol | LILACS | ID: lil-70014

RESUMO

En este trabajo se realiza un estudio de los tipos de imágenes de vigilia y de sueño que surgen en sujetos de experimentación bajo condiciones de privación sensorial a la vez que se les administra un estímulo sonoro, especialemtne un ritmo cardíaco electrónicamente obtenido, que actúa como inductor propioceptivo. Simultaneamente se toma um registro polisomnográfico con el fin de realizar una correlación entre el momento que surgen estas imágenes y los estados de conciencia que los fundan. El estudio permite una reelaboración del proceso de maduración y de formación de las imágenes en la mente, un replanteo semiológico de los tipos de imágenes, a la vez que una mayor comprensión de las funciones del yo durante el dormir, el soñar y durante las fases de transición hipnagógico-hipnopómpico. Finalmentea se toma en cuenta la importancia que tiene la relación interpersonal entre los sujetos y el equipo de investigación y su encuadre, el cual llega a modificar las características de los trazados de sueño


Assuntos
Adulto , Humanos , Masculino , Feminino , Nível de Alerta/fisiologia , Imaginação/fisiologia , Privação Sensorial , Sono/fisiologia , Eletrofisiologia , Relações Interpessoais , Psicoterapia
19.
Rev. argent. cir ; 49(6): 323-4, dic. 1985.
Artigo em Espanhol | LILACS | ID: lil-26768

RESUMO

Se presentan 12 casos de cáncer de la vesícula biliar, realizándose consideraciones sobre su diagnóstico, tratamiento y evolución y sobre la base del estadio tumoral


Assuntos
Pessoa de Meia-Idade , Humanos , Neoplasias da Vesícula Biliar
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