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991.
Elisabetta Marini Marco Marino Giulia Gionfriddo Federica Maione Marta Pandini Daniele Oddo Marta Giorgis Barbara Rolando Federica Blua Simone Gastaldi Serena Marchi Sandra Kovachka Francesca Spyrakis Eleonora Gianquinto Federica Di Nicolantonio Massimo Bertinaria 《Molecules (Basel, Switzerland)》2022,27(23)
BRAF is a serine/threonine kinase frequently mutated in human cancers. BRAFV600E mutated protein is targeted through the use of kinase inhibitors which are approved for the treatment of melanoma; however, their long-term efficacy is hampered by resistance mechanisms. The PROTAC-induced degradation of BRAFV600E has been proposed as an alternative strategy to avoid the onset of resistance. In this study, we designed a series of compounds where the BRAF kinase inhibitor encorafenib was conjugated to pomalidomide through different linkers. The synthesized compounds maintained their ability to inhibit the kinase activity of mutated BRAF with IC50 values in the 40–88 nM range. Selected compounds inhibited BRAFV600E signaling and cellular proliferation of A375 and Colo205 tumor cell lines. Compounds 10 and 11, the most active of the series, were not able to induce degradation of mutated BRAF. Docking and molecular dynamic studies, conducted in comparison with the efficient BRAF degrader P5B, suggest that a different orientation of the linker bearing the pomalidomide substructure, together with a decreased mobility of the solvent-exposed part of the conjugates, could explain this behavior. 相似文献
992.
Jorge R. Virus-Segovia Fernando Reyes Sandra Ruíz Jesús Martín Ignacio Fernndez-Pastor Carlos Justicia Mercedes de la Cruz Caridad Díaz Thomas A. Mackenzie Olga Genilloud Ignacio Gonzlez Jos R. Tormo 《Molecules (Basel, Switzerland)》2022,27(19)
Current needs in finding new antibiotics against emerging multidrug-resistant superbugs are pushing the scientific community into coming back to Nature for the discovery of novel active structures. Recently, a survey of halophilic actinomyectes from saline substrates of El Saladar del Margen, in the Cúllar-Baza depression (Granada, Spain), led us to the isolation and identification of 108 strains from the rhizosphere of the endemic plant Limonium majus. Evaluation of the potential of these strains to produce new anti-infective agents against superbug pathogens was performed through fermentation in 10 different culture media using an OSMAC approach and assessment of the antibacterial and antifungal properties of their acetone extracts. The study allowed the isolation of two novel antibiotic compounds, kribbellichelin A (1) and B (2), along with the known metabolites sandramycin (3), coproporphyrin III (4), and kribelloside C (5) from a bioassay-guided fractionation of scaled-up active extracts of the Kribbella sp. CA-293567 strain. The structures of the new molecules were elucidated by ESI-qTOF-MS/MS, 1D and 2D NMR, and Marfey’s analysis for the determination of the absolute configuration of their amino acid residues. Compounds 1–3 and 5 were assayed against a panel of relevant antibiotic-resistant pathogenic strains and evaluated for cytotoxicity versus the human hepatoma cell line HepG2 (ATCC HB-8065). Kribbellichelins A (1) and B (2) showed antimicrobial activity versus Candida albicans ATCC-64124, weak potency against Acinetobacter baumannii MB-5973 and Pseudomonas aeruginosa MB-5919, and an atypical dose-dependent concentration profile against Aspergillus fumigatus ATCC-46645. Sandramycin (3) confirmed previously reported excellent growth inhibition activity against MRSA MB-5393 but also presented clear antifungal activity against C. albicans ATCC-64124 and A. fumigatus ATCC-46645 associated with lower cytotoxicity observed in HepG2, whereas Kribelloside C (5) displayed high antifungal activity only against A. fumigatus ATCC-46645. Herein, we describe the processes followed for the isolation, structure elucidation, and potency evaluation of these two new active compounds against a panel of human pathogens as well as, for the first time, the characterization of the antifungal activities of sandramycin (3). 相似文献
993.
Verónica R. Elías Mónica E. Crivello Eduardo R. Herrero Sandra G. Casuscelli Griselda A. Eimer 《Journal of Non》2009,355(22-23):1269-1273
Two methods for the preparation of highly ordered MCM-41 silica are discussed. The quality of the structure was optimized by adequate stirring of the reaction mixture containing low concentration of surfactant, followed by heating at 70 °C for 3 h under stirring. Besides this energetically favorable procedure allowed to obtain structures very stable upon calcination. The role of the ethanol and the hydroxide source in the synthesis process is also analyzed. 相似文献
994.
A. Hantoute J. E. Martínez-Legaz 《Journal of Optimization Theory and Applications》2013,159(3):673-680
We give a necessary and sufficient condition for a difference of convex (DC, for short) functions, defined on a normed space, to be Lipschitz continuous. Our criterion relies on the intersection of the ε-subdifferentials of the involved functions. 相似文献
995.
996.
Gonzalo Martínez‐García Verónica Serafín Lourdes Agüí Paloma Yáñez‐Sedeño José M. Pingarrón 《Electroanalysis》2015,27(5):1119-1126
An electrochemical immunosensor for ghrelin (GHRL) determination in saliva is reported. Anti‐GHRL was immobilized onto Protein G‐magnetic beads and a competitive immunoassay involving biotinylated GHRL and alkaline phosphatase‐streptavidin was implemented. Once conjugate was magnetically captured on a screen‐printed carbon electrode, GHRL quantization was accomplished by DPV of 1‐naphtol formed upon addition of 1‐naphtyl phosphate. A linear range between 10?3 and 103 ng/mL GHRL, and a LOD of 7 pg/mL, much smaller than those from commercial ELISA kits, were found. The usefulness of the immunosensor was demonstrated by analyzing human saliva spiked with GHRL at 0.01, 0.1, 1 and 10 ng/mL. 相似文献
997.
We study one-dimensional Brownian motion with constant drift toward the origin and initial distribution concentrated in the strictly positive real line. We say that at the first time the process hits the origin, it is absorbed. We study the asymptotic behavior, ast, ofm
t
, the conditional distribution at time zero of the process conditioned on survival up to timet and on the process having a fixed value at timet. We find that there is a phase transition in the decay rate of the initial condition. For fast decay rate (subcritical case)m
t
is localized, in the critical casem
t
is located around
, and for slow rates (supercritical case)m
t
is located aroundt. The critical rate is given by the decay of the minimal quasistationary distribution of this process. We also study in each case the asymptotic distribution of the process, scaled by
, conditioned as before. We prove that in the subcritical case this distribution is a Brownian excursion. In the critical case it is a Brownian bridge attaining 0 for the first time at time 1, with some initial distribution. In the supercritical case, after centering around the expected value—which is of the order oft—we show that this process converges to a Brownian bridge arriving at 0 at time 1 and with a Gaussian initial distribution. 相似文献
998.
Fujisawa Kiyoshi Okano Mitsuki Martín-Pastor Manuel López-Sánchez Rubén Elguero José Alkorta Ibon 《Structural chemistry》2021,32(1):215-224
Structural Chemistry - Experimental multinuclear determination of the chemical shifts, especially 15N and 109Ag, of five silver(I) trinuclear pyrazolate complexes, (PzAg)3, coupled with ZORA... 相似文献
999.
Arsenic speciation is of increasing interest to the food industry, as concerns about high total arsenic concentrations in
food can often be alleviated to a great extent if the ratio of toxic, less toxic and non-toxic arsenic compounds in the sample
is known.
The lipid matrix of fish oil is a challenge in the determination of arsenic species, as current methods for this type of analysis
require the analyte to be water-soluble. In this study, two sample preparation techniques were applied. One the one hand water-soluble
species were extracted with methanol/water, on the other, acid digestion was applied to release lipid-soluble arsenic compounds
into the aqueous phase. Ion chromatography – inductively coupled plasma mass spectrometry (IC-ICP-MS) was used for separation
and sensitive element-specific detection of arsenic compounds. Additional experiments, including alkaline hydrolysis, were
carried out to find out more about the type of lipids arsenic is bound to in fish oil.
Up to eight different arsenic species were detected and quantified in fish oil with dimethylarsinate being the major compound
both in the aqueous extract and in the acid digest. No inorganic arsenic was detected in the aqueous extract, and the maximum
concentration of arsenate determined in the acid digest was 0.05 μg g−1.
The total arsenic concentration determined by ICP-MS ranged from <0.1 to 5 μg g−1. With regard to the mass balance, approximately 1% of the total arsenic content was extractable with methanol/water, whereas
the sum of arsenic species quantified after acid digestion yielded 85–100% of the total arsenic content. It was confirmed
that the large fraction of arsenic in fish oil not extractable on an aqueous basis consists of organoarsenic compounds.
This new approach in sample preparation makes the complete characterization of the arsenic content in the sample possible
with regard to the respective species, providing necessary information required for risk assessment. 相似文献
1000.
The major flavonoids present in the leaves and flowers of the cannabinoid-free cannabis (Cannabis sativa subsp. sativa L.) cultivars Felina and Futura are orientin (1), vitexin (2), luteolin-7-O-beta-D-glucuronide (3), and apigenin-7-O-beta-D-glucuronide (4), while prenylated flavonoids, to which the potent estrogenicity of hops (Humilus lupulus L.) is associated, are absent. The different composition of flavonoids has chemotaxonomic value. 相似文献