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1.
Wonsuk Chang Jinfa Du Suguna Rachakonda Bruce S. Ross Serge Convers-Reignier Wei T. Yau Jean-Francois Pons Eisuke Murakami Haiying Bao Holly Micolochick Steuer Phillip A. Furman Michael J. Otto Michael J. Sofia 《Bioorganic & medicinal chemistry letters》2010,20(15):4539-4543
Hepatitis C virus afflicts approximately 180 million people worldwide and currently there are no direct acting antiviral agents available to treat this disease. Our first generation nucleoside HCV inhibitor, RG7128 has already established proof-of-concept in the clinic and is currently in phase IIb clinical trials. As part of our continuing efforts to discover novel anti-HCV agents, 3′,4′-oxetane cytidine and adenosine nucleosides were prepared as inhibitors of HCV RNA replication. These nucleosides were shown not to be inhibitors of HCV as determined in a whole cell subgenomic replicon assay. However, 2′-mono/diflouro analogs, 4, 5, and 6 were readily phosphorylated to their monophosphate metabolites by deoxycytidine kinase and their triphosphate derivatives were shown to be inhibitors of HCV NS5B polymerase in vitro. Lack of anti-HCV activity in the replicon assay may be due to the inability of the monophosphates to be converted to their corresponding diphosphates. 相似文献
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Won Jun Choi Yu Min Kim Hea Ok Kim Hyuk Woo Lee Dong-Eun Kim Kwang-su Park Youhoon Chong Lak Shin Jeong 《Bioorganic & medicinal chemistry》2010,18(13):4812-4820
On the basis of potent anti-hepatitis C virus (HCV) activity of 2′-C-hydroxymethyladenosine, 3′-C-substituted-methyl-ribofuranosyl pyrimidine and purine nucleosides were designed and synthesized from d-xylose. Among compounds tested, all adenine analogues, 4a, 4d, and 4g showed significant anti-HCV activity in a replicon-based cell assay irrespective of the substituent (Y = OH, N3, or F) at the 3′-C-substituted methyl position, among which 4g (Y = N3) was the most potent, but it is also cytotoxic. This study guarantees the 3′-C-substituted-methyl nucleoside serves as a new template for the development of new anti-HCV agents. 相似文献
4.
Naveen C. Srivastav Michelle Mak Babita Agrawal D. Lorne J. Tyrrell Rakesh Kumar 《Bioorganic & medicinal chemistry letters》2010,20(22):6790-6793
Various 2,3′-anhydro analogs of 5-substituted 1-(2-deoxy-β-d-lyxofuranosyl)uracils (10–15) and a related 1-(3-O-mesyl-2-deoxy-β-d-lyxofuranosyl) pyrimidine nucleoside analog (18) have been synthesized for evaluation as a new class of potential anti-HBV agents. The compounds 10, 12, and 15 demonstrated most potent anti-HBV activities against duck HBV (DHBV) and human HBV with EC50 values in the range of 2.5–10 and 5–10 μg/mL, respectively, at non-toxic concentrations (CC50 = >200 μg/mL). The nucleoside 18 also demonstrated significant anti-HBV activity against DHBV with an EC50 value of 2.5 μg/mL, however, it was less active against HBV in 2.2.15 cells (EC50 = >10 μg/mL). 相似文献
5.
Noriko Yamaoka Yuko KudoKatsunori Inazawa Satoko InagawaMakoto Yasuda Ken-ichi MawatariKazuya Nakagomi Kiyoko Kaneko 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2010,878(23):2054-2060
A method using ion-pairing liquid chromatography–electrospray ionization (ESI)-mass spectrometry (MS) was developed for the simultaneous determination of 23 types of purine or pyrimidine nucleosides and nucleotides in dietary foods and beverages. Dihexylammonium acetate (DHAA) was used as an ion-pairing agent and an ultra performance liquid chromatography (UPLC™) system with a reversed-phase column and a gradient program was employed for the separation of nucleosides and nucleotides. Positive-ion ESI-MS was applied for the detection of nucleosides, and negative-ion ESI-MS was used for nucleotides. Lower limits of quantitation ranged from 0.02 μmol/L (UMP and AMP) to 1.3 μmol/L (CDP). The present method was validated, and sufficient reproducibility and accuracy was obtained for the quantitative measurement of the 23 types of nucleosides and nucleotides. The method was subsequently applied to their determination in a range of Japanese foods and beverages that are considered to contain significant amounts of umami flavor compounds. Because dietary purine nucleosides and nucleotides are known to be related to hyperuricemia and gout, the determination of their concentrations in dietary foods is useful for both evaluating umami flavor and assessing the effects of dietary food on purine metabolism. 相似文献
6.
Variable-temperature 220-MHz n.m.r. studies conducted on the 2′-deoxy derivatives of cytidine, thymidine, uridine, adenosine, guanosine, inosine and, to a limited extent, their 5′-phosphate disodium salts, allowed accurate proton-shift and coupling data to be obtained for the 2-deoxy-β-D-erythro-pentofuranosyl portion of the molecule. Conformational analysis, aided by the DAERM method, indicated that the sugar moiety of these molecules has a favored conformation 2V ? 2T3 ? V3 and an alternative favored conformation of 0V?0T4?V4. 相似文献
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3,5-Di-O-acetyl-6,7-dideoxy-1,2-O-isopropylidene-β-L-ido- and α-d-gluco-hept-6-ynofuranose were separately deacetonated, and the products acetylated, to give the 1,2,3,5-tetra-O-acetyl analogs (2 and 6). Fusion of compounds 2 and 6 with 2,6-dichloropurine under acid catalysis produced 2,6-dichloro-9-(2,3,5-tri-O-acetyl-6,7-dideoxy-α-L-ido-hept-6-ynofuranosyl)-9H-purine (3) and its β-d-gluco analog 7, respectively. Methanolic ammonia converted 3 in good yield into 2-chloro-9-(6,7-dideoxy-α-L-ido-hept-6-ynofuranosyl)-6-methoxy-9H-purine. Treatment of compound 3 with mesityl nitrile oxide gave a “double-headed nucleoside” analog. Upon treatment with phenyl azide, the d-gluco derivative 7 produced another “double-headed nucleoside”. Fusion of 2 and 6 with p-nitrophenol yielded the respective p-nitrophenyl glycosides. The stereochemistry and regiospecificity of the reactions were verified spectroscopically. 相似文献
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Histone mRNA, labeled with 32P or 3H-methionine during the S phase of partially synchronized HeLa cells, was isolated from the polyribosomes and purified as a “9S” component by sucrose gradient sedimentation. We identified two types of 5′ terminals, m7G(5′)pppNmpN and m7G(5′)pppNm-pNmpN, in which the first methylated nucleoside is 7-methylguanosine, the second is either N6,2′-O-dimethyladenosine, 2′-O-methyladenosine, or 2′-O-methylguanosine, and the third is 2′-O-methyluridine, 2′-O-methylcytidine, or 2′-O-methyladenosine. Approximately 1.7% of the 32P label was present in the 5′ terminal structures. Assuming a similar specific radioactivity for all phosphates, this percentage corresponds to an average of one terminal per 335 nucleotides. Histone mRNA differed from bulk polyadenylylated mRNA of HeLa cells in lacking significant amounts of 2′-O-methyluridine or 2′-O-methylcytidine in the second position of the 5′ terminal oligonucleotide and in lacking N6-methyladenosine residues at internal positions. 相似文献
9.
Zhe Chen Bryan D. Cox Ethel C. Garnier-Amblard Tamara R. McBrayer Steven J. Coats Raymond F. Schinazi Franck Amblard 《Bioorganic & medicinal chemistry letters》2017,27(23):5296-5299
Several β-d-2′-deoxy-2′-substituted nucleoside analogs have displayed potent and selective anti-HCV activities and some of them have reached human clinical trials. In that regard, we report herein the synthesis of a series of 2′-deoxy,2′-dibromo substituted U, C, G and A nucleosides 10a–d and their corresponding phosphoramidate prodrugs 13a–d. The synthesized nucleosides 10a–d and prodrugs 13a–d were evaluated for their inhibitory activity against HCV as well as cellular toxicity. The results showed that the most potent compound was prodrug 13a, which exhibited micromolar inhibitory activity (EC50?=?1.5?±?0.8?µM) with no observed toxicity. In addition, molecular modeling and free energy perturbation calculations for the 5′-triphosphate formed from 13a and related 2′-modified nucleotides are discussed. 相似文献
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David Beattie Andrew Brearley Zarin Brown Steven J. Charlton Brian Cox Robin A. Fairhurst John R. Fozard Peter Gedeck Paul Kirkham Koremu Meja Lana Nanson James Neef Helen Oakman Gillian Spooner Roger J. Taylor Robert J. Turner Ryan West Hannah Woodward 《Bioorganic & medicinal chemistry letters》2010,20(3):1219-1224
The synthesis of two series of 4′-aza-carbocyclic nucleosides are described in which the 4′-substituent is either a reversed amide, relative to the carboxamide of NECA, or an N-bonded heterocycle. Using established purine substitution patterns, potent and selective examples of agonists of the human adenosine A2A receptor have been identified from both series. The propionamides 14–18 and the 4-hydroxymethylpyrazole 32 were determined to be the most potent and selective examples from the 4′-reversed amide and 4′-N-bonded heterocyclic series, respectively. 相似文献
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The reaction of ImpA in the presence of Na+-montmorillonite 22A or Na+-Volclay in aqueous, pH 8 solution gives a 50–60% yield of dimers and trimers (pA)2 and (pA)3. The ratio of 3,5-phosphodiester bond formation is twice as great as 2,5-bond formation. The reaction requires the presence of Mg2+ and is inhibited by 0.4 M imidazole. N-methylimidazole enhances the rate of the reaction but does not cause major changes in yield or product composition. Higher yields were obtained when Li+- or Ca2+-montmorillonites were used in place of Na+-montmorillonite. Little or no phosphodiester bond formation was observed with Mg2+- or Al3+-montmorillonite. Montmorillonites other than 22A and Volclay exhibited little or no catalysis. In addition, little or no catalysis was exhibited in ferrugenous smectite, nontronite, allophane, imogolite or sepiolite. Oligomers were also formed by the reaction of ImpG, 2-methylImpG, ImpC and ImpU in the presence of Na+-montmorillonite. The pyrimidine nucleotides gave significantly lower yields of oligomers. 相似文献
12.
《Inorganica chimica acta》1988,151(4):243-248
The interactions of dimeric complex bis-[μ-chloro-chlorotricarbonylruthenium(II)], [Ru(CO)3Cl2]2, and the polymeric complex poly-[μ-dichlorodicarbonylruthenium(II)], [Ru(CO)2Cl2]x, with nucleosides (Nucl) in a 1:1 Ru:Nucl molar ratio for the dimer and 1:2 Ru:Nucl for the polymer, resulted in formation of the monomeric mononucleoside [Ru(CO)3(Nucl)Cl2] and bis-nucleoside [Ru(CO)2(Nucl)2Cl2] complexes, respectively. The dimer [Ru(CO)3Cl2]2 also gave the ionic bis-nucleoside complexes [Ru(CO)3(Nucl)2Cl]Cl in the molar ratio 1:2 Ru:Nucl. The mononucleoside complexes are stable in solution while the bis-nucleoside complexes tend to lose one nucleoside in strong complexing solvents, probably by solvent substitution. The complexes [Ru(CO)3(Nucl)Cl2] and [Ru(CO)2(Nucl)2Cl2] with one N(1)H ionizable imino proton undergo ionization in alkaline solution and the complexes [Ru(CO)3(NuclH+)Cl] and [Ru(CO)2(NuclH+)2], respectively, were isolated. In these deprotonated complexes the nucleosides behave as bidentate ligands, while in the protonated ones they act as monodentate. All Complexes were characterized by elemental analyses and various spectroscopic methods. 相似文献
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A yeast-mycelium (Y-M) transition in Candida albicans was induced by exogenous yeast extract, adenosine, adenosine 5-monophosphate (AMP), adenosine 5-diphosphate (ADP), adenosine 35 cyclic monophosphate (cAMP) and its analogue N6, O2-dibutyryl adenosine 35-cyclic monophosphate (dbcAMP) in defined liquid medium at 25°C. Adenosine 5-triphosphate (ATP) was found to delay germ tube formation in yeast cells, whereas the cAMP phosphodiesterase inhibitors, theophylline and caffeine, induced a Y-M transition. Intracellular and extracellular cyclic AMP levels increased during the yeast-mycelium transition and maximum levels of intracellular cyclic AMP coincided with maximum germ tube formation. Of the many inducers and inhibitors of germ tube and mycelium formation in C. albicans tested, including incubation at 37°C or in the presence of 1.5mM CaCl2, the calmodulin inhibitor calmidazolium (R24571) added together with CaCl2 induced the highest intra- and extracellular cyclic AMP levels. These results confirm the involvement of cyclic AMP in the yeast-mycelium transition of C. albicans. 相似文献
15.
Hong-wang Zhang Steven J. Coats Lavanya Bondada Franck Amblard Mervi Detorio Ghazia Asif Emilie Fromentin Sarah Solomon Aleksandr Obikhod Tony Whitaker Nicolas Sluis-Cremer John W. Mellors Raymond F. Schinazi 《Bioorganic & medicinal chemistry letters》2010,20(1):60-64
Based on the promising drug resistance profile and potent anti-HIV activity of β-d-3′-azido-2′,3′-dideoxyguanosine, a series of purine modified nucleosides were synthesized by a chemical transglycosylation reaction and evaluated for their antiviral activity, cytotoxicity, and intracellular metabolism. Among the synthesized compounds, several show potent and selective anti-HIV activity in primary lymphocytes. 相似文献
16.
Yurenko YP Zhurakivsky RO Samijlenko SP Hovorun DM 《Journal of biomolecular structure & dynamics》2011,29(1):51-65
The aim of this work is to cast some light on the H-bonds in double-stranded DNA in its AI and BI forms. For this purpose, we have performed the MP2 and DFT quantum chemical calculations of the canonical nucleoside conformers, relative to the AI and BI DNA forms, and their Watson-Crick pairs, which were regarded as the simplest models of the double-stranded DNA. Based on the atoms-in-molecules analysis (AIM), five types of the CH···O hydrogen bonds, involving bases and sugar, were detected numerically from 1 to 3 per a conformer: C2'H···O5', C1'H···O2, C6H···O5', C8H···O5', and C6H···O4'. The energy values of H-bonds occupy the range of 2.3-5.6 kcal/mol, surely exceeding the kT value (0.62 kcal/mol). The nucleoside CH···O hydrogen bonds appeared to "survive" turns of bases against the sugar, sometimes in rather large ranges of the angle values, pertinent to certain conformations, which points out to the source of the DNA lability, necessary for the conformational adaptation in processes of its functioning. The calculation of the interactions in the dA·T nucleoside pair gives evidence, that additionally to the N6H···O4 and N1···N3H canonical H-bonds, between the bases adenine and thymine the third one (C2H···O2) is formed, which, though being rather weak (about 1 kcal/mol), satisfies the AIM criteria of H-bonding and may be classified as a true H-bond. The total energy of all the CH···O nontraditional intramolecular H-bonds in DNA nucleoside pairs appeared to be commensurable with the energy of H-bonds between the bases in Watson-Crick pairs, which implies their possible important role in the DNA shaping. 相似文献
17.
Khalid J. Alzahrani Elena S. Matyugina Anastasia L. Khandazhinskaya Sergei N. Kochetkov Katherine L. Seley-Radtke Harry P. de Koning 《Bioorganic & medicinal chemistry letters》2017,27(14):3081-3086
Carbocyclic nucleoside analogues have a distinguished history as anti-infectious agents, including key antiviral agents. Toxicity was initially a concern but this was reduced by the introduction of 5′-nor variants. Here, we report the result of our preliminary screening of a series of 5′-norcarbocyclic uridine analogues against protozoan parasites, specifically the major pathogens Leishmania mexicana and Trypanosoma brucei. The series displayed antiparasite activity in the low to mid-micromolar range and establishes a preliminary structure-activity relationship, with the 4′,N3-di-(3,5-dimethylbenzoyl)-substituted analogues showing the most prominent activity. Utilizing an array of specially adapted cell lines, it was established that this series of analogues likely act through a common target. Moreover, the strong correlation between the trypanocidal and anti-leishmanial activities indicates that this mechanism is likely shared between the two species. EC50 values were unaffected by the disabling of pyrimidine biosynthesis in T. brucei, showing that these uridine analogues do not act directly on the enzymes of pyrimidine nucleotide metabolism. The lack of cross-resistance with 5-fluorouracil, also establishes that the carbocyclic analogues are not imported through the known uracil transporters, thus offering forth new insights for this class of nucleosides. The lack of cross-resistance with current trypanocides makes this compound class interesting for further exploration. 相似文献
18.
Kohei Yamada Hiroyuki Hayakawa Shinji Sakata Noriyuki Ashida Yuichi Yoshimura 《Bioorganic & medicinal chemistry letters》2010,20(20):6013-6016
We have identified a selective SN2′ reaction triggered by iodide ion that leads to the ring-opening of 2,2′-anhydro-α-nucleosides. By applying the method, we have synthesized α-d-2′,3′-didehydro-2′,3′-dideoxy-3′-C-hydroxymethyl nucleosides, designed as potential antiviral agents. 相似文献
19.
A M Bergman G Cristalli S Vittori J Wang S Eriksson G J Peters 《Nucleosides & nucleotides》1999,18(4-5):897-898
Several 1-deazapurine nucleosides were tested for their biological activity, anti-HIV-1, cytotoxicity and inhibition of adenosine deaminase (ADA). A2780 human ovarian cancer cells and the deoxycytidine kinase (dCK) deficient variant AG6000, used to determine whether dCK plays a role in their activation, showed a similar sensitivity to the analogs. This is in line with substrate specificity tests, which revealed a very low affinity of dCK. 相似文献