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1.
The effect of esterification at the 2'-position of desosamine on the antibacterial activity of erythromycin was investigated by determining the bacteriostatic and bactericidal activities of erythromycin and a number of its 2'-esters on S. aureus and relating these activities to the hydrolysis rates of the esters. These studies, together with comparison of the inhibition of protein synthesis in a cell-free system isolated from S. aureus, lead to the conclusion that 2'-esters of erythromycin are inactive until hydrolyzed. Loss of activity appears to result from inability of erythromycin esters to bind to bacterial ribosomes and thus inhibit synthesis of protein. 相似文献
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《Nucleosides, nucleotides & nucleic acids》2013,32(10):1899-1905
Abstract A convenient synthesis of 2′-deoxy-2-fluoroadenosine from commercially available 2-fluoroadenine is described. The coupling reaction of silylated 2-fluoroadenine with phenyl 3,5-bis[O-(t-butyldimethylsilyl)]-2-deoxy-1-thio-D-erythro-pentofuranoside gave the corresponding 2-fluoro-2′-deoxyadenosine derivative (α/β =1:1) in good yield. The α- and β-anomers were separated by chromatography, and then desilylated to give compounds 1a and 1b. 相似文献
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G. Cristalli S. Vittori A. Eleuteri R. Volpini E. Camaioni G. Lupidi 《Nucleosides, nucleotides & nucleic acids》2013,32(1-3):835-848
Abstract 5, 7-Dichloro-3H-imidazo[4, 5-b]pyridine (4) is a versatile base which can be coupled with a variety of sugar moieties and transformed in a series of 7-alkyl(aryl)amino-derivatives by reacting with the corresponding amines. In this paper synthesis, structure elucidation and ADA inhibitory activity of 2′-deoxyribonucleoside derivatives of N6-substituted 1-deazaapurines are described. 相似文献
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F. Bontemps C. Meier A. Delacauw J. Balzarini C. Galmarini E. Van Den Neste 《Nucleosides, nucleotides & nucleic acids》2013,32(9-11):997-1000
2-Chloro-2 ′-deoxyadenosine (CdA, cladribine) is a nucleoside analogue (NA) used for the treatment of lymphoproliferative disorders. Phosphorylation of the drug to CdAMP by deoxycytidine kinase (dCK) and its subsequent conversion to CdATP is essential for its efficacy. DCK deficiency is a common mechanism of resistance to NA, which could be overcome by the pronucleotide approach. The latter consists of using the nucleoside monophosphate conjugated to a lipophilic group enabling CdAMP to enter the cells by passive diffusion. In this study, we show that cycloSaligenyl-2-chloro-2 ′-deoxyadenosine monophosphate (cycloSal-CdAMP) is 10-fold more potent that CdA in a dCK-deficient lymphoma cell line. These results suggest that the use of cycloSal-nucleotides could be a strategy to counteract resistance caused by dCK deficiency. 相似文献
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Dong-Il Kim Mooseok Kang Sangyeol Kim Juhwan Lee Yongsoo Park Iksoo Chang Byung-Chang Suh 《Biophysical journal》2015,109(5):922-935
The auxiliary β subunit plays an important role in the regulation of voltage-gated calcium (CaV) channels. Recently, it was revealed that β2e associates with the plasma membrane through an electrostatic interaction between N-terminal basic residues and anionic phospholipids. However, a molecular-level understanding of β-subunit membrane recruitment in structural detail has remained elusive. In this study, using a combination of site-directed mutagenesis, liposome-binding assays, and multiscale molecular-dynamics (MD) simulation, we developed a physical model of how the β2e subunit is recruited electrostatically to the plasma membrane. In a fluorescence resonance energy transfer assay with liposomes, binding of the N-terminal peptide (23 residues) to liposome was significantly increased in the presence of phosphatidylserine (PS) and phosphatidylinositol 4,5-bisphosphate (PIP2). A mutagenesis analysis suggested that two basic residues proximal to Met-1, Lys-2 (K2) and Trp-5 (W5), are more important for membrane binding of the β2e subunit than distal residues from the N-terminus. Our MD simulations revealed that a stretched binding mode of the N-terminus to PS is required for stable membrane attachment through polar and nonpolar interactions. This mode obtained from MD simulations is consistent with experimental results showing that K2A, W5A, and K2A/W5A mutants failed to be targeted to the plasma membrane. We also investigated the effects of a mutated β2e subunit on inactivation kinetics and regulation of CaV channels by PIP2. In experiments with voltage-sensing phosphatase (VSP), a double mutation in the N-terminus of β2e (K2A/W5A) increased the PIP2 sensitivity of CaV2.2 and CaV1.3 channels by ∼3-fold compared with wild-type β2e subunit. Together, our results suggest that membrane targeting of the β2e subunit is initiated from the nonspecific electrostatic insertion of N-terminal K2 and W5 residues into the membrane. The PS-β2e interaction observed here provides a molecular insight into general principles for protein binding to the plasma membrane, as well as the regulatory roles of phospholipids in transporters and ion channels. 相似文献
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Takanori Miyashita Noriyuki Ashida Kazuhiko Kondoh Shinji Sakata Haruhiko Machida Akihiro Fujii 《Nucleosides, nucleotides & nucleic acids》2013,32(2-4):495-513
Abstract For the purpose of improvement of the in vivo antitumor activity of 2′-deoxy-2′-methylidenecytidine (DMDC, 1), we synthesized its various acyl and benzyl derivatives and evaluated them for their antitumor activity against P388 murine leukemia in mice. In terms of minimum effective dose (30% increase in life span), 5′-O-stearoyl DMDC showed two-fold higher antitumor activity than DMDC on a molar basis, when intraperitoneally (i.p.) administered to mice once a day. The antitumor activities of some other acyl derivatives were almost comparable to that of DMDC, while benzyl derivatives had no antitumor activity. Results on the hydrolysis of 5′-O-acyl derivatives by porcine liver esterase showed that at least these derivatives should not be resistant to enzymatic hydrolysis for exhibiting antitumor activity. After either an i.p. or oral dose of 3′-O-benzyl DMDC, very low concentrations of blood DMDC were seen compared with those after administration of DMDC, suggesting that the inactivity of benzyl derivatives as prodrugs was due to the minimal level of DMDC in circulation after administration. 相似文献
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The use of prostaglandins E2 and F2α, administered by extra-amniotic instillation, for the induction of abortion was studied in 94 patients in the first and second trimesters of pregnancy. Abortion was successfully induced in 87% of patients within 36 hours and in 94% within 48 hours. The mean abortion time was 22·4 hours. In 60% of patients abortion was complete.Though the differences were not statistically significant, on average multigravid patients aborted more quickly than primigravidae, while the mean abortion time in PGE2-treated patients was less than in those receiving PGF2α.No serious complications occurred. Some side effects were observed. Occasional vomiting was the commonest symptom but the incidence of side effects was lower than with alternative routes of administration. A leucocytosis was often noted but there were no significant instances of infection.The method has proved a safe and effective means of terminating pregnancies in the second trimester. 相似文献
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《Bioscience, biotechnology, and biochemistry》2013,77(9):1732-1736
Glucoamylases from Aspergillus niger and Rhizopus niveus catalyzed condensation of 2-deoxy-D-glucose (dGlc) to yield deoxy-glucooligosaccharides with polymerization degrees of 2–5. The enzymes also gave a small amount of products from 3-deoxy-o-glucose, but no products from 6-deoxy-D-glucose. A. niger α-glucosidase also catalyzed condensation of dGlc, while Torula and Saccharomyces α-glucosidases had low activity. α-l,4-, 1,6-, and 1,3-linked deoxy-glucobioses were isolated and identified as the products of A. niger glucoamylase and A. niger α-glucosidase. In the reaction of the glucoamylase, 1,4- and 1,3-linked saccharides decreased with an increase of 1,6-linked one. A. niger α-glucosidase produced α-1,6-linked disaccharide predominantly during the whole course of the reaction. 相似文献
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Sharon J Sequeira Huei Chi Wen Alvaro Avivar-Valderas Eduardo F Farias Julio A Aguirre-Ghiso 《BMC cell biology》2009,10(1):64
Background
The ErbB2/Her2/Neu receptor tyrosine kinase is amplified in ~30% of human breast cancers. Phosphorylation of the translation initiation factor, eIF2α inhibits global protein synthesis and activates a stress signaling and growth suppressive program. We have shown that forced phosphorylation of eIF2α can suppress head and neck, colorectal carcinoma and multiple myeloma tumor growth and/or survival. Here we explore whether ErbB2 modulates eIF2α phosphorylation and whether forced phosphorylation of the latter can antagonize ErbB2 deregulation of mammary acinar morphogenesis. 相似文献12.
Abstract 5-Ethyl-2′-deoxyurldine (EDU) is phosphorylated to a much greater extent by herpes simplex virus (HSV)-infected Vero cells than by mock-infected cells. Within the infected cells, EDU is preferentially incorporated into viral DNA and more inhibitory to viral than cellular DNA synthesis 相似文献
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Laureen C. Colis Debasis Chakraborti Pablo Hilario Christopher McCarty Ashis K. Basu 《Nucleosides, nucleotides & nucleic acids》2013,32(2):67-77
Two different approaches to synthesize oligonucleotides containing the 2 ′-deoxyguanosine adducts formed by nitropyrenes are described. A direct reaction of an unmodified oligonucleotide with an activated nitropyrene derivative is a convenient biomimetic approach for generating the major adducts in DNA. A total synthetic approach, by contrast, involves several synthetic steps, including Buchwald-Hartwig Pd-catalyzed coupling, but can be used for incorporating both the major and minor adducts in DNA in high yield. 相似文献
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Medium-chain length methyl ketones are potential blending fuels due to their cetane numbers and low melting temperatures. Biomanufacturing offers the potential to produce these molecules from renewable resources such as lignocellulosic biomass. In this work, we designed and tested metabolic pathways in Escherichia coli to specifically produce 2-heptanone, 2-nonanone and 2-undecanone. We achieved substantial production of each ketone by introducing chain-length specific acyl-ACP thioesterases, blocking the β-oxidation cycle at an advantageous reaction, and introducing active β-ketoacyl-CoA thioesterases. Using a bioprospecting approach, we identified fifteen homologs of E. coli β-ketoacyl-CoA thioesterase (FadM) and evaluated the in vivo activity of each against various chain length substrates. The FadM variant from Providencia sneebia produced the most 2-heptanone, 2-nonanone, and 2-undecanone, suggesting it has the highest activity on the corresponding β-ketoacyl-CoA substrates. We tested enzyme variants, including acyl-CoA oxidases, thiolases, and bi-functional 3-hydroxyacyl-CoA dehydratases to maximize conversion of fatty acids to β-keto acyl-CoAs for 2-heptanone, 2-nonanone, and 2-undecanone production. In order to address the issue of product loss during fermentation, we applied a 20% (v/v) dodecane layer in the bioreactor and built an external water cooling condenser connecting to the bioreactor heat-transferring condenser coupling to the condenser. Using these modifications, we were able to generate up to 4.4 g/L total medium-chain length methyl ketones. 相似文献
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Water diuresis was induced in six patients in mid-pregnancy. Three were then given oxytocin and the remainder prostaglandin F2α (PGF2α), both drugs being infused intravenously in doses used to induce labour at term. Pronounced antidiuresis occurred with oxytocin, whereas PGF2α showed no such effect. The probable absence of any risk of water intoxication when using PGF2α in inducing labour may be of particular value when maternal pre-eclampsia or renal disease is present. 相似文献
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A. I. Zinchenko V. N. Barai S. B. Bokut N. V. Dudchik E. I. Kvasyuk I. A. Mikhailopulo 《Biotechnology letters》1991,13(2):87-90
Summary The title compound was prepared by a two step enzymatic procedure consisting of DNA hydrolysis to the mixture of 2-deoxynucleosides followed by a transdeoxyribosilation of exogenous adenine. 相似文献
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Sergey N. Mikhailov Erik De Clercq Piet Herdewijn 《Nucleosides, nucleotides & nucleic acids》2013,32(7-8):1323-1334
Abstract The previously developed method for the preparation of 2′-O-D-ribofuranosyl-nucleosides is extended to ribosylation of 2′-deoxynucleosides. The scope and limitations of this reaction are discussed. 相似文献
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R.H. Abeles A.H. Tashjian S. Fish 《Biochemical and biophysical research communications》1980,95(2):612-617
S-Adenosylhomocysteinase (SAHase) is irreversibly inactivated by 2′-deoxyadenosine (Hirshfield, M.S. (1979) J. Biol. Chem. , 22–25). In the course of this inactivation, 2′dAd becomes tightly bound to the enzyme, i.e., cannot be removed by gel filtration or dialysis. Inactivation is accompanied by reduction of the enzyme bound NAD. When the inactivated enzyme is denatured, no 2′dAd is recovered. Adenine equivalent to about 80% of the bound 2′dAd is isolated. It is proposed that 2′-deoxyadenosine is first oxidized to 3′-keto-2-deoxyadenosine by enzyme bound NAD. The 3′keto group activates the hydrogen at C-2′ and facilitates elimination of adenine. 相似文献