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21.
P Galéra D Vivien S Pronost J Bonaventure F Rédini G Loyau J P Pujol 《Journal of cellular physiology》1992,153(3):596-606
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There is a great deal of current interest in the role and importance of chirality in the development of new drugs, but little attention is being paid to the stereochemistry of older drugs. Indeed, many older chiral drugs were introduced without adequate information on their stereochemical identity or composition. We have examined one such drug, the antihypertensive diuretic agent cyclothiazide. Standard sources of drug information and the research literature do not provide data on the stereochemical composition of clinically used cyclothiazide, although scattered reports indicate that the drug may consist of "several stereoisomers." Inspection of the chemical structure of the drug, 6-chloro-3,4-dihydro-3-(5-norbornen-2-yl)-2H-1,2,4-benzothiadiazin e-7- sulfonamide 1,1-dioxide, shows that it can exist as eight stereoisomers that may form four racemates. Using synthesis, fast-atom-bombardment mass spectrometry, gas-liquid chromatography, chiral and nonchiral high-performance liquid chromatography, and nuclear magnetic resonance spectroscopy, we determined that pharmaceutical cyclothiazide is in fact a mixture of the eight stereoisomers in the form of the four racemates. The two racemates with endo configuration at the norbornene moiety predominate over the exo racemates, and small but significant differences in isomer distribution between different batches of the drug were observed. We urge that in studies of older drugs the stereochemical details be considered. 相似文献
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Verónica Corrales-Sánchez María del Mar Noblejas-López Cristina Nieto-Jiménez Javier Pérez-Peña Juan Carlos Montero Miguel Burgos Eva M. Galán-Moya Atanasio Pandiella Alberto Ocaña 《Journal of cellular and molecular medicine》2020,24(5):3117-3127
Identification of druggable vulnerabilities is a main objective in triple-negative breast cancer (TNBC), where no curative therapies exist. Gene set enrichment analyses (GSEA) and a pharmacological evaluation using a library of compounds were used to select potential druggable combinations. MTT and studies with semi-solid media were performed to explore the activity of the combinations. TNBC cell lines (MDAMB-231, BT549, HS-578T and HCC3153) and an additional panel of 16 cell lines were used to assess the activity of the two compounds. Flow cytometry experiments and biochemical studies were also performed to explore the mechanism of action. GSEA were performed using several data sets (GSE21422, GSE26910, GSE3744, GSE65194 and GSE42568), and more than 35 compounds against the identified functions were evaluated to discover druggable opportunities. Analyses done with the Chou and Talalay algorithm confirmed the synergy of dasatinib and olaparib. The combination of both agents significantly induced apoptosis in a caspase-dependent manner and revealed a pleotropic effect on cell cycle: Dasatinib arrested cells in G0/G1 and olaparib in G2/M. Dasatinib inhibited pChk1 and induced DNA damage measured by pH2AX, and olaparib increased pH3. Finally, the effect of the combination was also evaluated in a panel of 18 cell lines representative of the most frequent solid tumours, observing a particularly synergism in ovarian cancer. Breast cancer, triple negative, dasatinib, olaparib, screening. 相似文献
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A. Tăbăran V. A. Balteanu E. Gal D. Pusta R. Mihaiu S. D. Dan 《Animal biotechnology》2013,24(2):105-111
Milk and dairy products are considered the main sources of saturated fatty acids, which are a valuable source of nutrients in the human diet. Fat composition can be adjusted through guided nutrition of dairy animals but also through selective breeding. Recently, a dinucleotide substitution located in the exon 8 of the gene coding for acyl CoA: diacylglycerol acyltransferase 1 (DGAT1), that alters the amino acid sequence from a lysine to an alanine (p.Lys232Ala) in the mature protein, was shown to have a strong effect on milk fat content in some cattle breeds. Therefore, the objectives of this work were to study the occurrence of the DGAT1 p.Lys232Ala polymorphism in Romanian Holstein cattle and Romanian Buffalo breeds and to further investigate its possible influence on fat percentage and fatty acid profiles. The results obtained in this study show that in Romanian Holstein cattle the K allele is associated with increased fat percentage and higher levels of C16:0 and C18:0 fatty acids. The ratio of saturated fatty acids versus unsaturated fatty acids (SFA/UFA) was also higher in KK homozygous individuals, whereas the fractions of C14:0, unsaturated C18 decreased. The DGAT1 p.Lys232Ala polymorphism revealed a high genetic variance for fat percentage, unsaturated C18, C16:0, and SFA/UFA. Although the effect of this polymorphism was not so evident for short chain fatty acids such as C4:0–C8:0, it was significant for C14:0 fatty acids. We concluded that selective breeding of carriers of the A allele in Romanian Holsteins can contribute to improvement in unsaturated fatty acids content of milk. However, in buffalo, the lack of the A allele makes selection inapplicable because only the K allele, associated with higher saturated fatty acids contents in milk, was identified. 相似文献
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M. Bueno Martínez E. Román Galán J. A. Galbis Pérez 《Nucleosides, nucleotides & nucleic acids》2013,32(2):227-244
Abstract Fusion of 2-trimethylsilylpyridine and tetra-O-acetyl-aldehydo-D-xylose or 2,3:4,5-di-O-isopropylidene-aldehydo-L-arabinose led, after removing of the protecting groups, to 2-(pentitol-1-yl)pyridines of D-gulo and D-ido or L-manno configurations. Dehydration of the sugar-chain with D-gulo and D-ido configurations gave the corresponding 2′,5′-anhydro derivatives, whereas 2-(5-O-isopropyl-L-manno-pentitol-1-yl)-pyridine was the only compound formed by dehydration of the sugar-chain with L-manno configuration. Structural proofs are based on 1H and 13C NMR spectra. 相似文献
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Guadalupe Galíndez Pablo Ortega-Baes Ana L. Scopel Michael J. Hutchings 《Plant Ecology》2013,214(1):75-86
A model was developed to assess how the seed rain and fire regime affect seed bank dynamics and seedling establishment of three native shrub species (Acanthostyles buniifolius, Baccharis pingraea and Baccharis dracunculifolia) with different regeneration strategies, in temperate South American savanna. Seed bank and seed rain were quantified for each species under different fire regimes, and their relative roles in regeneration were evaluated. All species had short-term persistent seed banks and high annual variability in seed production. A high proportion of seeds deposited in the seed rain produced seedlings after fire; few entered the soil seed bank. Fire killed a high proportion of the seeds in the soil seed bank. Seedlings derived from the seed rain had a higher probability of surviving for 2 years than seedlings emerging from the soil seed bank. In the absence of fire, establishment depended on germination both from the seed rain and the soil seed bank, whereas with annual fire, establishment was primarily dependent on germination of seeds arriving in the annual seed rain, regardless of species’ regeneration strategies. These results help to explain changes in the vegetation of South American temperate savannas as a result of changes in fire regime and grazing management during the last 50 years. By revealing the crucial roles of the soil seed bank and seed rain in regeneration, this study provides vital information for the development of appropriate management practices to control populations of shrub species with different regeneration strategies in South American temperate savannas. 相似文献
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Esther García‐Fernández Daniel J. Frank Beatriz Galán Petrea M. Kells Larissa M. Podust José L. García Paul R. Ortiz de Montellano 《Environmental microbiology》2013,15(8):2342-2359
Degradation of the cholesterol side‐chain in Mycobacterium tuberculosis is initiated by two cytochromes P450, CYP125A1 and CYP142A1, that sequentially oxidize C26 to the alcohol, aldehyde and acid metabolites. Here we report characterization of the homologous enzymes CYP125A3 and CYP142A2 from Mycobacterium smegmatis mc2 155. Heterologously expressed, purified CYP125A3 and CYP142A2 bound cholesterol, 4‐cholesten‐3‐one, and antifungal azole drugs. CYP125A3 or CYP142A2 reconstituted with spinach ferredoxin and ferredoxin reductase efficiently hydroxylated 4‐cholesten‐3‐one to the C‐26 alcohol and subsequently to the acid. The X‐ray structures of both substrate‐free CYP125A3 and CYP142A2 and of cholest‐4‐en‐3‐one‐bound CYP142A2 reveal significant differences in the substrate binding sites compared with the homologous M. tuberculosis proteins. Deletion only of cyp125A3 causes a reduction of both the alcohol and acid metabolites and a strong induction of cyp142 at the mRNA and protein levels, indicating that CYP142A2 serves as a functionally redundant back up enzyme for CYP125A3. In contrast to M. tuberculosis, the M. smegmatis Δcyp125Δcyp142 double mutant retains its ability to grow on cholesterol albeit with a diminished capacity, indicating an additional level of redundancy within its genome. 相似文献
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