共查询到20条相似文献,搜索用时 15 毫秒
1.
2.
3.
4.
5.
6.
7.
Photooxidation of d(TpG) by riboflavin and methylene blue. Isolation and characterization of thymidylyl-(3',5')-2-amino-5-[(2-deoxy-beta-D- erythro-pentofuranosyl)amino]-4H-imidazol-4-one and its primary decomposition product thymidylyl-(3',5')-2,2-diamino-4-[(2-deoxy-beta-D- erythro-pentofuranosyl)amino]-5(2H)-oxazolone. 下载免费PDF全文
The major initial product of riboflavin- and methylene blue-mediated photosensitization of 2'-deoxyguanosine (dG) in oxygen-saturated aqueous solution has previously been identified as 2-amino-5-[(2-deoxy-beta-D-erythro-pentofuranosyl)amino] 4H-imidazol-4-one (dlz). At room temperature in aqueous solution dlz decomposes quantitatively to 2,2-diamino-4-[(2-deoxy-beta-D-erythro- pentofuranosyl)amino]-5(2H)-oxazolone (dZ). The data presented here show that the same guanine photooxidation products are generated following riboflavin- and methylene blue-mediated photosensitization of thymidylyl-(3',5')-2'-deoxyguanosine [d(TpG)]. As observed for the monomers, the initial product, thymidylyl-(3',5')-2-amino-5-[(2-deoxy- beta-D-erythro-pentofuranosyl)amino]-4H-imidazol-4-one [d(Tplz)], decomposes in aqueous solution at room temperature to thymidylyl-(3',5')-2,2-diamino-4- [(2-deoxy-beta-D-erythro-pentofuranosyl)amino]-5(2H)-oxazolone [d(TpZ)]. Both modified dinucleoside monophosphates have been isolated by HPLC and characterized by proton NMR spectrometry, fast atom bombardment mass spectrometry, chemical analyses and enzymatic digestions. Among the chemical and enzymatic properties of these modified dinucleoside monophosphates are: (i) d(Tplz) and d(TpZ) are alkali-labile; (ii) d(Tplz) reacts with methoxyamine, while d(TpZ) is unreactive; (iii) d(Tplz) is digested by snake venom phosphodiesterase, while d(TpZ) is unaffected; (iv) relative to d(TpG), d(TpZ) and d(Tplz) are slowly digested by spleen phosphodiesterase; (v) d(Tplz) and d(TpZ) can be 5'-phosphorylated by T4 polynucleotide kinase. The first observation suggests that dlz and dZ may be responsible for some of the strand breaks detected following hot piperidine treatment of DNA exposed to photosensitizers. 相似文献
8.
Conformational analysis of (2R,3S,4R)-(+)-3,3',4,4',7-flavanpentol, a flavonoid compound displaying both antioxidant and pro-oxidant properties, is performed by molecular mechanics and density functional theory calculations both in the gas phase and in methanol solution by using the Polarizable Continuum Model. Nine different conformations are identified. Absorption (UV) and circular dichroism (CD) spectra and optical rotations are calculated by means of time dependent density functional theory (TDDFT) and compared with experiments. The effects of a complex environment formed by water and proline-rich peptide molecules on the conformational characteristics of (2R,3S,4R)-(+)-3,3',4,4',7-flavanpentol and therefore on its UV and CD spectra are investigated by atomistic molecular dynamics simulations. 相似文献
9.
Li LS Zhou Y Murphy DE Stankovic N Zhao J Dragovich PS Bertolini T Sun Z Ayida B Tran CV Ruebsam F Webber SE Shah AM Tsan M Showalter RE Patel R Lebrun LA Bartkowski DM Nolan TG Norris DA Kamran R Brooks J Sergeeva MV Kirkovsky L Zhao Q Kissinger CR 《Bioorganic & medicinal chemistry letters》2008,18(11):3446-3455
5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. Lead optimization led to the discovery of compound 3a, which displayed potent inhibitory activities in biochemical and replicon assays [IC(50) (1b)<10nM; IC(50) (1a)=22 nM; EC(50) (1b)=5nM], good stability toward human liver microsomes (HLM t(1/2)>60 min), and high ratios of liver to plasma concentrations 12h after a single oral administration to rats. 相似文献
10.
An asymmetric synthesis route towards (3S,3'S)-(M,M)-(E)-(+)-1,1',2, 2',3,3',4,4'-octahydro-3,3',7,7'-tetramethyl-4,4'-biphenanthrylidene was developed using the Evans procedure as a key step. The absolute configurations of the title compound and of its parent ketone were determined by CD spectroscopy and could be correlated with the stereochemical results of the asymmetric alkylation. Furthermore, a comparison was made with the known (3R,3'R)-(P,P)-(E)-(-)-1,1',2,2', 3,3',4,4'-octahydro-3,3',7,7'-dimethyl-4,4'-biphenanthrylidene. Finally, the X-ray crystallographic analysis of (3S,3'S)-(M, M)-(E)-(+)-1,1',2,2',3,3',4,4'-octahydro-3,3',7,7'-tetramethyl-4, 4'-biphenanthrylidene is presented. 相似文献
11.
Lavandera I Fernández S Ferrero M De Clercq E Gotor V 《Nucleosides, nucleotides & nucleic acids》2003,22(5-8):833-836
(E)-3',5'-diamino-5-(2-bromovinyl)-2',3',5'-trideoxyuridine (5), the diamino analogue of BVDU (1), was synthesized from BVDU. In contrast with BVDU, compound 5 did not show activity against herpes simplex virus or varicella-zoster virus. 相似文献
12.
Dragovich PS Blazel JK Ellis DA Han Q Kamran R Kissinger CR LeBrun LA Li LS Murphy DE Noble M Patel RA Ruebsam F Sergeeva MV Shah AM Showalter RE Tran CV Tsan M Webber SE Kirkovsky L Zhou Y 《Bioorganic & medicinal chemistry letters》2008,18(20):5635-5639
The synthesis of 4-(1',1'-dioxo-1',4'-dihydro-1'lambda(6)-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones bearing 6-amino substituents as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC(50)<0.10 microM). In vitro DMPK data (microsome t(1/2), Caco-2 P(app)) for many of the compounds are also disclosed, and a crystal structure of a representative inhibitor complexed with the NS5B protein is discussed. 相似文献
13.
14.
Zhou Y Webber SE Murphy DE Li LS Dragovich PS Tran CV Sun Z Ruebsam F Shah AM Tsan M Showalter RE Patel R Li B Zhao Q Han Q Hermann T Kissinger CR Lebrun L Sergeeva MV Kirkovsky L 《Bioorganic & medicinal chemistry letters》2008,18(4):1413-1418
5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. The synthesis, structure-activity relationships (SAR), metabolic stability, and structure-based design approach for this new class of compounds are discussed. 相似文献
15.
C S Owen 《Analytical biochemistry》1992,204(1):65-71
The dyes carboxy-SNARF-1 and BCECF are fluorescent probes of intracellular pH that exhibit changes in spectral shape upon proton binding which allow one to use measurements of fluorescence at two or more wavelengths in order to measure pH without artifacts associated with variability in dye loading, etc. In evaluating these dyes for this study, whole spectra, rather than measurements at two wavelengths, were analyzed. For BCECF, the effects of the intracellular milieu were minimal: both the pH-sensitive excitation spectrum and the pKa agreed closely with values found in extracellular solution. In contrast, both the spectra and the pKa for the emission spectrum-shifting carboxy-SNARF-1 showed significant differences between intracellular and extracellular dye. As a result, extremely misleading values for intracellular pH will be obtained if one attempts to use extracellular dye to calibrate intracellular carboxy-SNARF-1 measurements. Multiple origins were found for the discrepancy: (i) the intracellular dye was found to be significantly quenched, with the deprotonated form being more strongly quenched than the protonated form; and (ii) the pKa for the equilibrium with intracellular hydrogen ions was shifted by +0.2 pH units. These effects were readily reversed by disruption of the cell, but were not due to sequestering of dye in an acidic cell compartment. 相似文献
16.
Zhou Y Li LS Dragovich PS Murphy DE Tran CV Ruebsam F Webber SE Shah AM Tsan M Averill A Showalter RE Patel R Han Q Zhao Q Hermann T Kissinger CR Lebrun L Sergeeva MV 《Bioorganic & medicinal chemistry letters》2008,18(4):1419-1424
5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. The structure-activity relationship (SAR) associated with variation of the pyridazinone 2- and 6-substituents is discussed. The synthesis and metabolic stability of this new class of compounds are also described. 相似文献
17.
Xie L Allaway G Wild C Kilgore N Lee KH 《Bioorganic & medicinal chemistry letters》2001,11(17):2291-2293
Six 3-substituted 3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone derivatives (3-8) were synthesized from 3-methyl DCK (2). 3-Hydroxymethyl DCK (6) exhibited potent anti-HIV activity in H9 lymphocytes with EC(50) and TI values of 1.87 x 10(-4) microM and 1.89 x 10(5), respectively. These values are similar to those of DCK and better than those of AZT in the same assay. 相似文献
18.
Sergeeva MV Zhou Y Bartkowski DM Nolan TG Norris DA Okamoto E Kirkovsky L Kamran R Lebrun LA Tsan M Patel R Shah AM Lardy M Gobbi A Li LS Zhao J Bertolini T Stankovic N Sun Z Murphy DE Webber SE Dragovich PS 《Bioorganic & medicinal chemistry letters》2008,18(11):3421-3426
5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as potent inhibitors of genotype 1 HCV NS5B polymerase focusing on the optimization of their drug metabolism and pharmacokinetics (DMPK) profiles. This investigation led to the discovery of potent inhibitors with improved DMPK properties. 相似文献
19.
20.
A summary delineating the large scale synthetic studies to prepare labeled precursors of ribonucleosides-3',4',5',5'-2H4 and -2',3',4',5',5'-2H5 from D-glucose is presented. The recycling of deuterium-labeled by-products has been devised to give a high overall yield of the intermediates and an expedient protocol has been elaborated for the conversion of 3-O-benzyl-alpha,beta-D-allofuranose-3,4-d2 6 to 1-O-methyl-3-O-benzyl-2-O-t-butyldimethylsilyl-alpha,beta-D-ribofuranose-3,4,5,5'-d4 16 (precursor of ribonucleosides-3',4',5',5'-2H4) or to 1-O-methyl-3,5-di-O-benzyl-alpha,beta-D-ribofuranose-3,4,5,5'-d4 18 (precursor of ribonucleosides-3',4',5',5'-2H4). 相似文献