Very efficient and broad-in-scope palladium-catalyzed Hiyama cross-coupling: The role of water and copper(I) salts

A very high-yielding Pd-catalyzed cross-coupling between aryl halides and aryl(trialkoxy)silanes is achieved in the presence of Cu(i) and a measured amount of water. This novel methodology is useful for the generation of a wide range of biaryls, particularly non-para substituted derivatives, which are usually less reported.Fil: Traficante, Carla Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; ArgentinaFil: Mata, Ernesto Gabino. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; ArgentinaFil: Delpiccolo, Carina Maria Lujan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentin

フラクタルと地理学

The prevalence of subclinical hepatic encephalopathy (SHE) varies according to the diagnostic tool used in its detection. Since a standardised approach to the diagnosis of SHE is not yet available, we compared psychometric tests and EEG spectral analysis. On the same day 32 cirrhotic patients without overt hepatic encephalopathy and 18 controls were assessed by psychometric tests, both standard and computerized (CPT), and by EEG spectral analysis (EEG-SA). The CPT, measuring reaction time (Rt) and errors (er), were Font, Choice1, Choice2 and Scan test. The standard psychometric tests were the number connection test (NCT), the Reitan-B test, the Line Tracing Test [for time: LTT(t) and for errors: LTT(er)], and the Symbol Digit test (SD). Both psychometric tests [Reitan-B test, LTT(er) and CPT but Font (Rt) and Choice2 (er)] and EEG-SA parameters [mean dominant frequency (MDF) and theta power (0%)] significantly correlated (p<0.05) with albumin plasma levels. LTT(er), Scan, Font, Choice1 and Choice2 were significantly related to 0% and MDF. There was no control with positive EEG-SA, though one control was positive with LTT(t) and with the number of errors made during Font and Scan tests. The percentage of cirrhotics with positive EEG-SA was 34% (CI(95%)=19-53), while 9-66% were positive with psychometric tests, depending on the test considered. In spite of the correlation between neuropsychological and neurophysiological parameters, the diagnostic agreement between EEG-SA and each psychometric test was not high. In conclusion: 1) neurophysiological and neuropsychological impairment in cirrhotics without overt hepatic encephalopathy were found linked to each other and to hepatic dysfunction; 2) psychometric tests were not sufficiently good predictors of EEG alterations; therefore, neuropsychological tools can not substitute neurophysiological ones to detect CNS dysfunction in liver disease

Synergistic antitumor effect of a penicillin derivative combined with thapsigargin in melanoma cells

Purpose: To investigate the effect of TAP7f, a penicillin derivative previously characterized as a potent antitumor agent that promotes ER stress and apoptosis, in combination with thapsigargin, an ER stress inducer, on melanoma cells. Methods: The synergistic antiproliferative effect of TAP7f in combination with thapsigargin was studied in vitro in murine B16-F0 melanoma cells, and in human A375 and SB2 melanoma cells. In vivo assays were performed with C57BL/6J mice challenged with B16-F0 cells. Immunofluorescence and Western blot assays were carried out to characterize the induction of ER stress and apoptosis. Necrotic tumor areas and the potential toxicity of the combined therapy were examined by histological analysis of tissue sections after hematoxylin-eosin staining. Results: In vitro, the combination of TAP7f with thapsigargin synergistically inhibited the proliferation of murine B16-F0, and human A375 and SB2 melanoma cells. When non-inhibitory doses of each drug were simultaneously administered to C57BL/6J mice challenged with B16-F0 cells, a 50% reduction in tumor volumes was obtained in the combined group. An apoptotic response characterized by higher expression levels of Baxenhanced PARP-1 cleavage and the presence of active caspase 3 was observed in tumors from the combined treatment. In addition, higher expression levels of GADD153/CHOP and ATF4 were found in tumors of mice treated with both drugs with respect to each drug used alone, indicating the induction of an ER stress response. No signs of tissue toxicity were observed in histological sections of different organs extracted from mice receiving the combination. Conclusion: The synergistic and effective antitumor action of TAP7f in combination with thapsigargin could be considered as a potential therapeutic strategy for melanoma treatment.Fil: Bellizzi, Yanina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Cornier, Patricia Griselda. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; ArgentinaFil: Delpiccolo, Carina Maria Lujan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; ArgentinaFil: Mata, Ernesto Gabino. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; ArgentinaFil: Blank, Viviana Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Roguin, Leonor Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; Argentin

Mechanism of action of a triazolyl peptidyl penicillin in melanoma cells and synergistic antitumor effect of its combination with thapsigargin

In a previous study, we demonstrated that TAP7f, a synthetic triazolylpeptidyl penicillin, induces an apoptotic response and behaves as an effective antitumor agent in murine melanoma cells. In this work, we comparatively examined its mechanism of action in murine B16-F0 and human A375 melanoma cells. We first studied the contribution of an endoplasmic reticulum (ER) stress response to the apoptotic effect induced by the derivative. To this end, the expression levels of different ER stress-related proteins were evaluated by Western blot assays in both melanoma cell lines. A significant increase in the amount of ATF4, GADD153/CHOP, calnexin and GRP78/BIP was observed after incubating B16-F0 cells for 3 h or 6 h with a 20 µM concentration of TAP7f. A similar effect was observed in A375 cells for some of these ER markers. It was also shown that TAP7f increased phosphorylation levels of p38, JNK and Akt in both melanoma cell lines. Based on the effectiveness of combined therapies for cancer treatment, we decided to investigate the in vitro antiproliferative effect of TAP7f with thapsigargin, a well-known ER stress activator. The simultaneous incubation of different concentrations of both compounds showed a higher inhibition of cell growth with respect to the effect of each individual agent both in B16-F0 and A375 melanoma cells. The quantitative analysis of dose-effect curves obtained by using the Compusyn software rendered combination indexes lower than 1 (0.48-0.62 for B16-F0 and 0,41-0.76 for A375), indicating synergism. In conclusion, we showed that induction of ER stress and activation of p38, JNK and PI3K-I/Akt pathways are involved in the antitumor effect induced by TAP7f in melanoma cells. The efficacy of the combination of TAP7f with thapsigargin suggested that this therapy could be considered an auspicious tool for melanoma treatment.Fil: Anselmi Relats, Juan Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Bellizzi, Yanina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Cornier, Patricia Griselda. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; ArgentinaFil: Delpiccolo, Carina Maria Lujan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; ArgentinaFil: Mata, Ernesto Gabino. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; ArgentinaFil: Blank, Viviana Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Roguin, Leonor Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaLXVI Reunión anual de la Sociedad Argentina de Investigación Clínica; LXIX Reunión anual de la Sociedad Argentina de Inmunología; LIII Reunión Anual de la Asociación Argentina de Farmacología Experimental y XI Reunión Anual de la Asociación Argentina de NanomedicinasArgentinaSociedad Argentina de Investigación ClínicaSociedad Argentina de InmunologíaAsociación Argentina de Farmacología ExperimentalAsociación Argentina de Nanomedicina

Garbage in, garbage out: how reliable training data improved a virtual screening approach against SARS-CoV-2 MPro

Introduction: The identification of chemical compounds that interfere with SARS-CoV-2 replication continues to be a priority in several academic and pharmaceutical laboratories. Computational tools and approaches have the power to integrate, process and analyze multiple data in a short time. However, these initiatives may yield unrealistic results if the applied models are not inferred from reliable data and the resulting predictions are not confirmed by experimental evidence.Methods: We undertook a drug discovery campaign against the essential major protease (MPro) from SARS-CoV-2, which relied on an in silico search strategy –performed in a large and diverse chemolibrary– complemented by experimental validation. The computational method comprises a recently reported ligand-based approach developed upon refinement/learning cycles, and structure-based approximations. Search models were applied to both retrospective (in silico) and prospective (experimentally confirmed) screening.Results: The first generation of ligand-based models were fed by data, which to a great extent, had not been published in peer-reviewed articles. The first screening campaign performed with 188 compounds (46 in silico hits and 100 analogues, and 40 unrelated compounds: flavonols and pyrazoles) yielded three hits against MPro (IC50 ≤ 25 μM): two analogues of in silico hits (one glycoside and one benzo-thiazol) and one flavonol. A second generation of ligand-based models was developed based on this negative information and newly published peer-reviewed data for MPro inhibitors. This led to 43 new hit candidates belonging to different chemical families. From 45 compounds (28 in silico hits and 17 related analogues) tested in the second screening campaign, eight inhibited MPro with IC50 = 0.12–20 μM and five of them also impaired the proliferation of SARS-CoV-2 in Vero cells (EC50 7–45 μM).Discussion: Our study provides an example of a virtuous loop between computational and experimental approaches applied to target-focused drug discovery against a major and global pathogen, reaffirming the well-known “garbage in, garbage out” machine learning principle

Solid-Phase Organic Chemistry: Synthesis of 2β-(Heterocyclylthiomethyl)Penam Derivatives on Solid Support

Abstract: The synthesis of 2β-(heterocyclylthiomethyl)penam derivatives on solid support has been developed. Compounds are obtained in good to high yields (based on loading of the original resin). The key step is the solid-phase double rearrangement of the corresponding penicillin sulfoxide

Immobilized boronic acid for Suzuki–Miyaura coupling: application to the generation of pharmacologically relevant molecules

An synthetic strategy for the generation of a variety of biaryl and related derivatives, based on Suzuki– Miyaura coupling using immobilized boronic acid, is described. The importance of the methodology was demonstrated by its further application to biologically interesting compounds such as 4-biaryl-blactams, descripted as cholesterol absorption inhibitors and anti-MRSA active agents, neoflavonoids, imidazoles, isoxazolines, among others.This is a post-peer-review, pre-copyedit version of an article published in RSC Advances. The final authenticated version is available online at: https://doi.org/10.1039/c7ra06662gFil: Martinez-Amezaga, Maitena. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario (IQUIR -CONICET); Argentina.Fil: Delpiccolo, Carina M. L. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario (IQUIR -CONICET); Argentina.Fil: Mata, Ernesto Gabino. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario (IQUIR -CONICET); Argentina