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PubMed1995

Site-selected introduction of modified purine and pyrimidine ribonucleosides into RNA by automated phosphoramidite chemistry.

The study of modified nucleoside contributions to RNA chemistry, structure and function has been thwarted by the lack of a site-selected method of incorporation which is both versatile and adaptable to present synthetic technologies. A reproducible and versatile site-selected incorporation of nine differently modified nucleosides into hepta- and octadecamer RNAs has been achieved with automated phosphoramidite chemistry. The 5'-O-(4,4'-dimethoxytrityl-2'-O-tert-butyldimethylsilyl-ribonucleoside- 3'-O-(2-cyanoethyl-N,N-diisopropyl)phosphoramidite syntheses of m5C, D, psi, riboT, s2U, mnm5U, m1G and m2A were designed for compatibility with the commercially available major and 2'OH methylated ribonucleoside phosphoramidites. The synthesis of the m5C phosphoramidite was uniquely designed, and the first syntheses and incorporation of the two modified purine ribonucleosides are reported in detail along with that of psi, s2U, and mnm5U. Cleavage of RNA product from the synthesis support column, deprotection of the RNA, its purification by HPLC and nucleoside composition analysis are described. Modified nucleoside-containing tRNA domains were synthesized and purified in mumol quantities required for biophysical, as well as biochemical, studies. The anticodon domain of yeast tRNA(Phe) was synthesized with modified nucleosides introduced at the native positions: Cm32, Gm34, m1G37 (precursor to Y), psi 39 and m5C40. The T loop and stem was synthesized with riboT54 and the D loop and stem with D16 and D17. The E coli tRNA(Glu2) anti-codon codon domain was synthesized with mnm5U at wobble position 34, but an attempt at incorporating s2U at the same position failed. The unprotected thio group was labile to the oxidation step of the cyclical process. Chemically synthesized anticodon and T domains have been used in assays of tRNA structure and function (Guenther et al (1994) Biochimie 76, 1143-1151).

Amides↗
PubMed1998

Cell proliferation induced by 8-oxoguanosine and 8-methylguanosine, two adducts produced by free radical attack on ribonucleosides and RNA.

The ability of C8-substituted guanine (Gua) ribonucleosides to induce B cell proliferation has been well documented in the literature. These compounds are analogues of adducts formed from free radical attack on ribonucleosides and RNA. Here we examined the proliferative properties of two of these radical adducts, 8-methylguanosine (8-MeG) and 8-oxo-7,8-dihydroguanosine (8-OxoG) and compared them with those of the well studied B cell mitogen, 8-bromoguanosine (8-BrG). 8-MeG and 8-OxoG were synthesized in the considerable yields of 28, and 55%, respectively, and were characterized by UV, NMR and CG-MS. Their effects upon [3H]thymidine uptake into DNA by Swiss mouse splenocytes, mouse embryo 3T3 fibroblasts (A31) and mouse B16F10 melanoma were examined. Both guanosine (G) radical adducts were shown to increase [3H]thymidine uptake by mouse splenocytes but displayed selectivity in respect to continuous cell lines. 8-MeG acted upon 3T3 fibroblasts whereas 8-OxoG acted upon B16F10 melanoma. The non-physiological analogue 8-BrG acted upon all tested cells. Parallel experiments of cell counting, cytotoxicity,and cell sorting indicated that DNA synthesis induced by the C8-substituted G's reflected cell growth. It is proposed that the compounds act intracellularly because their proliferative effects were blocked in the presence of a nucleoside transport inhibitor but were not inhibited by an antagonist of the A2 purine receptor. The present results, taken together with data from the literature, suggest that in the case of 3T3 fibroblasts and mouse splenocytes the proliferative effects of the compounds are not dependent on metabolism through purine salvage pathways. In the case of melanoma, however, the compounds are likely to become part of the purine nucleoside pool. The demonstration that adducts produced by free radical attack on ribonucleosides and RNA are able to induce cell proliferation opens new perspectives for the understanding of free radical mediated carcinogenesis.

3T3 Cells↗
PubMed2004

Structure-activity relationship of heterobase-modified 2'-C-methyl ribonucleosides as inhibitors of hepatitis C virus RNA replication.

Hepatitis C virus infection constitutes a significant health problem in need of more effective therapies. We have recently identified 2'-C-methyladenosine and 2'-C-methylguanosine as potent nucleoside inhibitors of HCV RNA replication in vitro. However, both of these compounds suffered from significant limitations. 2'-C-Methyladenosine was found to be susceptible to enzymatic conversions by adenosine deaminase and purine nucleoside phosphorylase, and it displayed limited oral bioavailability in the rat. 2'-C-Methylguanosine, on the other hand, was neither efficiently taken up in cells nor phosphorylated well. As part of an attempt to address these limitations, we now report upon the synthesis and evaluation of a series of heterobase-modified 2'-C-methyl ribonucleosides. The structure-activity relationship within this series of nucleosides reveals 4-amino-7-(2-C-methyl-beta-d-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine and 4-amino-5-fluoro-7-(2-C-methyl-beta-d-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine as potent and noncytotoxic inhibitors of HCV RNA replication. Both 4-amino-7-(2-C-methyl-beta-d-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine and 4-amino-5-fluoro-7-(2-C-methyl-beta-d-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine display improved enzymatic stability profiles as compared to that of 2'-C-methyladenosine. Consistent with these observations, the most potent compound, 4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine ribonucleoside, is orally bioavailable in the rat. Together, the potency of the 2'-C-methyl-4-amino-pyrrolo[2,3-d]pyrimidine ribonucleosides and their improved pharmacokinetic properties relative to that of 2'-C-methyladenosine suggests that this class of compounds may have clinical utility.

Adenosine Deaminase↗
PubMed2003

Studies towards the large scale chemical synthesis of the precursors of ribonucleosides-3',4',5',5''-2H4 and -2',3',4',5',5''-2H5.

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).

Deuterium↗
PubMed1982

Selective 2'-benzoylation at the cis 2',3'-diols of protected ribonucleosides. New solid phase synthesis of RNA and DNA-RNA mixtures.

5'-0-(Dimethoxytrityl)-2'-0-(benzoyl or 3,4,5-trimethoxybenzoyl)-base protected ribonucleosides have been prepared by selective benzoylation of the 2'-hydroxyl group. The isomerization of the 2'-benzoates to the 3'-benzoates was studied. The protected ribonucleosides have been converted to either methylphosphochloridites or methylphosphoamidites and used to synthesize oligoribonucleotides on silica gel solid support. The synthetic RNA were deprotected and isolated using conditions that minimize internucleotide cleavage. The use of 2'-benzoates as protecting groups for ribonucleosides has made it possible to easily prepare and isolate mixtures of DNA and RNA.

Benzoates↗
PubMed2003

In vitro activities of benzimidazole D- and L-ribonucleosides against herpesviruses.

Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), and human herpesvirus 8 (HHV-8) are responsible for a number of clinical manifestations in both normal and immunocompromised individuals. The parent benzimidazole ribonucleosides evaluated in this series, 2-bromo-5,6-dichloro-1-(beta-D-ribofuranosyl)benzimidazole (BDCRB) and maribavir (1263W94), are potent and selective inhibitors of human CMV replication. These nucleosides act by two different mechanisms. BDCRB blocks the processing and maturation of viral DNA, whereas 1263W94 inhibits the viral enzyme pUL97 and interferes with DNA synthesis. In the present study, we have evaluated the in vitro antiviral activity of BDCRB, an analog, GW275175X (175X), and 1263W94 against the replication of HSV-1, HSV-2, VZV, CMV, EBV, HHV-6, and HHV-8. By using various methodologies, significant activity was observed against human CMV and EBV but not against HSV-1, HSV-2, VZV, HHV-6, or HHV-8. Plaque reduction assays performed on a variety of laboratory and clinical isolates of human CMV indicated that all strains, including those resistant to ganciclovir (GCV) and foscarnet, were sensitive to all three benzimidazole ribonucleosides, with mean 50% effective concentration values of about 1 to 5 microM compared to that of GCV at 6 microM. The toxicity of these compounds in tissue culture cells appeared to be similar to that observed with GCV. These results demonstrate that the benzimidazole ribonucleosides are active against human CMV and EBV and suggest that they may be useful for the treatment of infections caused by these herpesviruses.

Antiviral Agents↗
PubMed1990

[Ribonucleosides in milk: characterization and determination of the concentration profile of these minor components throughout a lactation period].

The ribonucleosides adenosine, cytidine, guanosine, inosine and uridine as well as the modified components N1-methyladenosine and N6-carbamoylthreonyladenosine were characterized and determined quantitatively as minor constituents in raw bovine milk by use of an automated high performance liquid chromatography system. The studies have shown that except for the colostral phase the ribonucleoside levels are constant throughout the whole lactation period. That means, there is a typical ribonucleoside pattern which is assumed to be species-specific.

Animals↗
PubMedDate not supplied

Ribonucleosides in human milk. Concentration profiles of these minor constituents as a function of the nursing time.

Ribonucleosides are secreted as products of cellular RNA and ribonucleotide metabolism into physiological fluids such as blood, milk and urine. Unmodified and modified ribonucleosides have been detected in the micromolar range as minor constituents in the milk of different mammals. In addition to the common nucleosides adenosine, cytidine, guanosine, inosine and uridine, modified components such as 1-methyladenosine, 1-methylguanosine, 1-methylinosine, N2-methylguanosine, N2-dimethylguanosine, N6-carbamoyl-L-threonyladenosine, pseudouridine and 5-aminoimidazole-4-carboxamide-N-ribofuranoside (AICAR) have been identified and most of them quantified in samples of human and/or bovine and/or goat's milk. From these investigations it is known that nucleosides, in analogy to nucleotides, show a typical species-specific pattern. Longitudinal studies have been carried out to determine the concentration profiles of the individual ribonucleosides in the milk of humans as a function of the nursing time.

Animals↗
PubMed1991

Formation and morphology of helical structures from phospholipid-ribonucleoside conjugates in an acidic solution.

Phospholipid-ribonucleoside conjugates containing two myristoyl groups and a ribonucleotidyl group, dimyristoyl-5'-phosphatidyl-ribonucleosides, have been synthesized, and their self-organization and morphology have been investigated in acidic solutions. In acidic solutions, dimyristoyl-5'-phosphatidyl-ribonucleosides produced much different helical structures from those produced in neutral and alkaline solutions.

Hydrogen-Ion Concentration↗
PubMed1988

Selective killing of glucose-deprived hypoxic cells by hyperthermia. I. Protection by purine ribonucleosides.

Energy deprivation increases sensitivity to killing by hyperthermia. Hypoxic cells become dramatically sensitive to heat under glycolytic inhibition or glucose deprivation. To define the role of glucose metabolism in hypoxic cells in the presence or absence of elevated temperatures, cell culture studies were carried out to determine whether the enhanced cell killing of glucose-deprived hypoxic cells could be reversed by nucleoside supplementation. The results with HeLa cells showed that purine ribonucleosides were capable of reversing the enhanced heat-induced cytotoxicity under appropriate cultural conditions. Pyrimidine ribonucleosides and deoxyribonucleosides were ineffective. Based on the known metabolism of purine ribonucleosides, it is postulated that protection from hyperthermic killing by purine nucleosides comes about as a result of increased energy production via the purine nucleotide cycle.

Cell Survival↗
PubMed1988

Interaction of vanadyl ribonucleoside complex with the androgen receptor.

The addition of vanadyl ribonucleoside complex (VRC), a potent inhibitor of RNase, to the transformed 4.5S androgen receptor from rat submandibular gland caused an increase in the sedimentation coefficient to 7.0S. Moreover, VRC decreased the DNA-cellulose binding of the transformed receptor; 50% inhibition of the DNA-cellulose binding was achieved at 1.8 mM VRC. On the other hand, agents related to VRC and oxoanions of transient metals, such as ribonucleoside, vanadate, molybdate, tungstate and arsenate, exerted no effect on the DNA-cellulose binding ability of the receptor. These findings suggest that VRC binds to the transformed androgen receptor at the DNA-binding site and that both oxovanadium ion and ribonucleoside are indispensable for the binding of VRC to the transformed androgen receptor.

Animals↗
PubMed1982

Coupled ribonucleoside diphosphate reduction, channeling, and incorporation into DNA of mammalian cells.

There is rapid and specific channeling of ribonucleoside diphosphates into DNA through reactions beginning with ribonucleotide reductase and terminating with DNA polymerase. Lysolecithin-permeabilized Chinese hamster embryo fibroblasts in culture rapidly reduced ribonucleoside diphosphates by ribonucleotide reductase action when dithiothreitol was provided as a reducing agent and incorporated these deoxynucleotides into DNA. The radioactive label provided in ribo-CDP was not diluted by added deoxyribo-CTP during its incorporation into DNA, showing that the ribo-CDP does not pass through a deoxy-CTP pool. Under the conditions that permitted rapid incorporation of ribonucleoside diphosphates, deoxynucleoside triphosphates were very poorly incorporated. Ribonucleotide reductase with the rate-limiting enzyme for the overall process. The Km values for the reductase reaction and the overall process were similar and low enough for saturation by in vivo pools. Natural feedback inhibitors dATP or dTTP inhibited incorporation of labeled ribo-CDP into deoxyribonucleotides and into DNA to the same extent. Ribonucleotide reductase behaved like other enzymes that are associated in a rapidly sedimenting form. It was concentrated in the nucleus during S phase, and most of the enzyme activity in these nuclear extracts was co-sedimented with DNA polymerase on sucrose density gradients. These data support the hypotheses that a physically associated complex of enzymes (replitase) catalyzes the production of deoxynucleotides and their incorporation into DNA in S phase cells.

Animals↗
PubMed1980

The purification and characterization of an adenosylcobalamin-dependent ribonucleoside diphosphate reductase from Corynebacterium nephridii.

A deoxyadenosylcobalamin-dependent ribonucleoside diphosphate reductase has been purified to homogeneity from cell free extracts of Corynebacterium nephridii. Ion exchange chromatography of th extract on DEAE-Sephadex and DEAE-Bio-Gel A, followed by affinity chromatography on dGTP-Sepharose, yielded two forms of the reductase. The first reductase, which was weakly bound to the affinity column, was eluted with 0.1 M citrate buffer, pH 6.5, while the second, more tightly bound form required 2 M urea for its elution. The weakly bound form is homogeneous as judged by gel filtration, equilibrium sedimentation, and polyacrylamide gel electrophoresis. This enzyme is a dimeric protein with a molecular weight of 196,000, composed of two identical or very similar subunits with molecular weights of 100,000. The second protein appears to be a polymeric form of the reductase. Both forms of the enzyme catalyze the reduction of the four common ribonucleoside diphosphates as well as the hydrogen exchange between adenosylcobalamin and the solvent. The ribonucleoside diphosphate reductase system of C. nephridii appears to be intermediate between the more "primitive" adenosylcobalamin-dependent reductase system of Lactobacillus leichmannii and the more "advanced" nonheme iron system of Escherichia coli.

Amino Acid Sequence↗
PubMed1981

Possible regulation of ribonucleoside diphosphate reductase.

Two inhibitors of ribonucleoside diphosphate reductase (RR) (EC 1.17.4.1) in vitro were isolated from normal rat liver: they were a nondialyzable, heat-labile, high-molecular-weight ribonucleoside diphosphate reductase inhibitor (HRRI, and a dialyzable, heat-stable, low-molecular-weight ribonucleoside diphosphate reductase inhibitor (LRRI). The activities of both inhibitors varied inversely with the cell growth rate. HRRI from the cytosol fraction of rat liver was partially purified by ammonium sulfate fractionation (0 - 50%), and gel filtration on a Sepharose 6B column. It was eluted in the void volume from this column, together with ATP-hydrolyzing activity. The HRRI fraction also contained CDP kinase and CDPase activities, suggesting that HRRI is a complex of several enzymes that reduce the concentrations of the substrate of RR, CDP, and of the allosteric activator, ATP. LRRI was extracted from the cytosol of rat liver with ethanol (80% final concentration) and purified further by washing with organic solvent, and be chromatographies of Amberlite IR-45 and Dowex 50. Finally, it was identified as glucose, which was phosphorylated to glucose 6-phosphate by hexokinase present tin the RR enzyme solution ( 0 - 35% ammonium sulfate fraction of AH-130 cytosol), thus causing ATP depletion. Thus, neither inhibitor reacted directly with the RR enzyme, but both may regulate the enzyme activity in vivo by reducing the intracellular levels of substrates or cofactors.

Animals↗
PubMed1995

Synthesis of [5'-11C]ribonucleoside and -2'-deoyribonucleoside derivatives from D-ribose.

An approach to the synthesis of 2'-deoxy[5'-13C]ribonucleosides was achieved by the coupling reaction of a nucleic acid base derivative with D-[5-13C]ribose derivative (8). Compound 8 was derived from D-ribose (1) by way of methyl 2,3-di-O-benzyl(Bn)-D-ribofuranoside (2), 2,3-di-O-Bn-D-ribose diethyl dithioacetal (3), 2,3-di-O-Bn-D-ribose dibenzyl acetal (4), and 4-aldehydo-2,3-di-O-Bn-D-erythrose dibenzyl acetal (5), which was then successively subjected to Wittig reaction using Ph3P13CH3I-BuLi, highly stereoselective hydroxylation with OsO4 to give 2,3-di-O-Bn-D-ribose dibenzyl acetal (7), debenzylation with H2-Pd/C. The resulting 8 was subjected to coupling reaction with a nucleic acid base to give [5'-13C]ribonucleosides. The products were derived into the corresponding 2'-deoxy[5'-13C]ribonucleoside derivatives by the established manner.

Carbon Isotopes↗
PubMed1990

Pyrimidine ribonucleoside catabolism in Pseudomonas fluorescens biotype A.

The pyrimidine ribonucleosides uridine or cytidine were shown to serve as a source of nitrogen or carbon for the growth of Pseudomonas fluorescens strain A126. After incubation of either pyrimidine ribonucleoside with extracts of this strain, the resultant catabolic products were detected by thin-layer chromatography. It was found that pyrimidine ribonucleoside catabolism in this pseudomonad involved the enzymes nucleoside hydrolase and cytosine deaminase. The specific activities of both these enzymes could be influenced by the nitrogen or carbon source present in the medium.

Carbon↗
PubMed1983

Determination of ribonucleoside triphosphate pools in influenza A virus-infected MDCK cells.

A rapid method for determining the concentration of ribonucleoside triphosphates in cell cultures is described. The pool sizes of the ribonucleoside triphosphates in uninfected MDCK cells were found to be, 0.28-0.59 mM CTP, 0.96-1.6 mM UTP, 6.5-7.8 mM ATP, and 1.1-1.4 mM GTP, depending on the condition of the cell-monolayer. Infection of MDCK cells with influenza A strains Victoria 3/75 x-47 or WSN resulted in insignificant changes in the ribonucleoside triphosphate concentrations. Treatment of infected and non-infected MDCK cells with ribavirin caused a decrease of 60 per cent in the GTP pool.

Adenosine Triphosphate↗
PubMed2006

Characterization of reactions of antimoniate and meglumine antimoniate with a guanine ribonucleoside at different pH.

It has been shown previously that Sb(V) forms mono- and bis-adducts with adenine and guanine ribonucleosides, suggesting that ribonucleosides may be a target for pentavalent antimonial drugs in the treatment of leishmaniasis. In the present work, the reactions of antimoniate (KSb(OH)(6)) and meglumine antimoniate (MA) with guanosine 5'-monophosphate (GMP) have been characterized at 37 degrees C in aqueous solution and two different pH (5 and 6.5), using ESI(-)-MS and (1)H NMR. Acid and base species for both 1:1 and 1:2 Sb(V)-GMP complexes were identified by ESI(-)-MS. The (1)H NMR anomeric region was explored for determining the concentrations of mono- and bis-adducts. This allows for the determination of stability constants for these complexes (5,900 L mol(-1) for 1:1 complex and 370 L mol(-1) for 1:2 complex, at pD 5 and 37 degrees C). Kinetic studies at different pH indicated that formation and dissociation of both 1:1 and 1:2 Sb-GMP complexes are slow processes and favored at acidic pH (2,150 L mol(-1) h(-1) for the rate constant of 1:1 complex formation and 0.25 h(-1) for the rate constant of 1:1 complex dissociation, at pD 5 and 37 degrees C). When MA was used, instead of antimoniate, formation of 1:1 Sb-GMP complex occurred, but with a slower rate constant. Assuming that MA consists essentially of a 1:1 Sb-meglumine complex, a stability constant for MA could also be estimated (8,600 L mol(-1) at pD 5 and 37 degrees C). Thermodynamic and kinetic data are consistent with the formation of 1:1 Sb-ribonucleoside complexes in vertebrate hosts, following treatment with pentavalent antimonial drugs.

Animals↗