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PubMed1994

The antimitotic drug 4,6-dimethyl-2-amino-3,4,5- trimethoxyphenyl-pyrimidine inhibits the nucleoside transport system of cells from various animal species.

4,6-dimethyl-2-amino-3,4,5-trimethoxyphenyl-pyrimidine (B-31) is a pyrimidine derivative previously reported to arrest the mitotic cycle of mammalian cells in metaphase. In the present study it is shown that B-31 also acts as a specific inhibitor of the cellular uptake of nucleosides. The uptake of purinic and pyrimidinic nucleosides is inhibited by 80-90% at concentrations in the range 5-20 micrograms/ml, whereas those of nucleobases, leucine, choline and glucose are unaltered at the maximum nontoxic dose of B-31 (25 micrograms/ml). Various mammalian (human, monkey and murine) and avian cell are equally sensitive to the inhibition of nucleoside transport. The antimitotic effect of B-31, by contrast, is species-specific: human cells are the most sensitive whereas monkey and chicken fibroblasts appear resistant to this effect. Both effects can be reversed by removal of B-31 from the medium; inhibition of nucleoside transport can also be reversed by high doses of the nucleosides themselves.

Animals↗

PubMed2002

Nucleoside transporters in absorptive epithelia.

There are two families of nucleoside transporters, concentrative (termed CNTs) and equilibrative (called ENTs). The members of both families mediate the transmembrane transport of natural nucleosides and some drugs whose structure is based on nucleosides. CNT transporters show a high affinity for their natural substrates (with Km values in the low micromolar range) and are substrate selective. In contrast, ENT transporters show lower affinity and are more permissive regarding the substrates they accept. Both types of transporters are tightly regulated in all cell types studied so far, both by endocrine and growth factors and by substrate availability. The degree of cell differentiation and the proliferation status of a cell also affect the pattern of expressed transporters. Although the presence of both types of transporters in the cells of absortive epithelia suggested the possibility of a transepithelial flux of nucleosides, their exact localization in the different plasma membrane domains of epithelial cells had not been demonstrated until recently. Concentrative transporters are found in the apical membrane while equlibrative transporters are located in the basolateral membrane, thus strengthening the hypothesis of a transepithelial flux of nucleosides.

Animals↗

PubMed2003

The purine nucleoside cycle in cell-free extracts of rat brain: evidence for the occurrence of an inosine and a guanosine cycle with distinct metabolic roles.

The purine nucleoside cycle is a cyclic pathway composed of three cytosolic enzymes, hypoxanthine-guanine phosphoribosyltransferase, IMP-GMP specific 5'-nucleotidase, and purine-nucleoside phosphorylase. It may be considered a 'futile cycle', whose net reaction is the hydrolysis of 5-phosphoribosyl-1-pyrophosphate to inorganic pyrophosphate and ribose 1-phosphate. The availability of a highly purified preparation of cytosolic 5'-nucleotidase prompted us to reconstitute the purine nucleoside cycle. Its kinetics were strikingly similar to those observed when dialyzed extracts of rat brain were used. Thus, when the cycle is started by addition of inorganic phospate (Pi) and hypoxanthine or inosine (the 'inosine cycle'), steady-state levels of the intermediates are observed and the cycle 'turns over' as far as 5-phosphoribosyl-1-pyrophosphate is being consumed. In the presence of ATP, which acts both as an activator of IMP-GMP-specific 5'-nucleotidase and as substrate of nucleoside mono- and di-phosphokinases, no IDP and ITP are formed. The inosine cycle is further favored by the extremely low xanthine oxidase activity. Evidence is presented that ribose 1-phosphate needed to salvage pyrimidine bases in rat brain may arise, at least in part, from the 5-phosphoribosyl-1-pyrophosphate hydrolysis as catalyzed by the inosine cycle, showing that it may function as a link between purine and pyrimidine salvage. When the cycle is started by addition of Pi and guanine (the 'guanosine cycle'), xanthine and xanthosine are formed, in addition to GMP and guanosine, showing that the guanosine cycle 'turns over' in conjunction with the recycling of ribose 1-phosphate for nucleoside interconversion. In the presence of ATP, GDP and GTP are also formed, and the velocity of the cycle is drastically reduced, suggesting that it might metabolically modulate the salvage synthesis of guanyl nucleotides.

Animals↗

PubMed1988

Reactivity of pyrimidine nucleosides under the conditions of the pyrimidine sequencing reactions of Maxam and Gilbert.

Several pyrimidine nucleosides and polydeoxyribonucleotides have been examined with respect to their ultraviolet absorption spectra and the kinetics of their decomposition under the conditions used in the C- and (C + T)-specific treatments of the sequencing procedure of Maxam and Gilbert. In hydrazine-water (56:44, v/v), at 20 degrees C, thymidine was found to be virtually fully ionized. Under these conditions, the susceptibility to hydrazinolysis decreased in the order N3-methylthymidine greater than uridine approximately equal to deoxyuridine greater than deoxycytidine approximately equal to polydeoxycytidylate greater than polythymidylate much greater than thymidine greater than 5-methyldeoxycytidine. Addition of sodium chloride to 1.5 M slightly accelerated hydrazinolysis of those nucleosides bearing nonionizable heterocyclic moieties and retarded hydrazinolysis severalfold for those nucleosides containing an ionizable aglycone (thymidine, deoxyuridine, uridine). It is concluded that the nucleosides of this latter class react with hydrazine largely or exclusively in their nonionized form and that the main effect of added salt is increased ionization of the heterocycles, resulting in a decreased population of nonionized nucleosides.

Base Sequence↗

PubMed1991

Saccharomyces cerevisiae nucleoside-diphosphate kinase: purification, characterization, and substrate specificity.

Nucleoside-diphosphate kinase is an enzyme which catalyzes the phosphorylation of nucleoside diphosphates into the corresponding triphosphates for nucleic acid biosynthesis. In this communication, we describe the purification and characterization of nucleoside-diphosphate kinase from yeast. The purified protein appears to be homogeneous by sodium dodecyl sulfate-polyacrylamide gel analysis, with a molecular weight of about 17,000-18,000. An estimate from the fast protein liquid chromatography Superose 12 gel filtration shows a native molecular weight of about 68,000 to 70,000. The results suggest that yeast nucleoside-diphosphate kinase is composed of four subunits. Substrate specificity studies show that the relative activity of nucleoside diphosphates (NDP) as phosphate acceptors is in the order of dTDP greater than CDP greater than UDP greater than dUDP greater than GDP greater than or equal to dGDP greater than dCDP greater than dADP greater than ADP; and the relative activity of triphosphate donors is in the order of UTP greater than dTTP greater than CTP greater than dCTP greater than dATP greater than ATP greater than or equal to dGTP greater than GTP. The Km and Vm of dTDP, dGDP, dCDP, dUDP, CDP, and UDP have been determined. The rate constant studies indicate that the purified NDP kinase prefers using, to a slight extent, dTDP (approximately 800 min-1) as the substrate rather than other tested deoxyribo- and ribonucleotides (350-450 min-1). The broad substrate specificity and kinetic data suggest that the enzyme is involved in both DNA and RNA metabolism.

Molecular Weight↗

PubMed1984

The role of protein phosphokinase and protein phosphatase during the nuclear envelope nucleoside triphosphatase reaction.

The activities of nuclear envelope-associated protein phosphokinase and protein phosphatase were determined in nuclear ghosts from liver and oviduct of quails. The protein kinase was found to be inhibited by poly(A) by 75%. During the kinase reaction proteins with molecular weights of 106 000 and 64 000 were phosphorylated. The phosphoprotein phosphatase from liver was stimulated to 190% by poly(A), whereas only a slight enhancing effect by this polymer was determined with the oviduct enzyme (to 125%). Comparative determinations of the nuclear ghost-associated enzyme activities revealed the following values (in nmol Pi/min per 10(8) ghosts); oviduct: phosphokinase, 0.015; phosphatase, 0.004 and nucleoside triphosphatase, 39.4; and liver: phosphokinase, 0.044; phosphatase, 0.012 and nucleoside triphosphatase, 11.7. These data indicate that phosphorylation/dephosphorylation proceeds independently of the nucleoside triphosphatase cycle. This assumption is supported by analytical results revealing that no marked dephosphorylation occurs after poly(A) binding to the nuclear envelope. Moreover, stoichiometrical data showed a nearly 1:1 molar ratio between ATP-binding and phosphorylation of nuclear envelope protein. From these findings a new model for the nucleoside triphosphatase-mediated poly(A)(+)mRNA efflux from nuclei is deducted, proposing phosphokinase and phosphatase only to modulate the affinity of the 'carrier structure' for poly(A) (+)mRNA, but not to constitute the nucleoside triphosphatase.

Animals↗

PubMed1995

Production of adenosine and nucleoside analogs by the exchange reaction catalyzed by rat liver adenosine kinase.

We have previously shown [8] that rat liver adenosine kinase can produce [14C]AMP from [14C]adenosine (Ado) and unlabelled adenosine monophosphate (AMP), in the absence of ATP, by an exchange reaction. In this study, we investigated whether Ado or AMP could be replaced in this exchange reaction by other nucleosides or nucleoside monophosphates (NMP), respectively. In the presence of 1 mM of the unlabelled NMP analogs 7-deazaadenosine (tubercidin) 5'-monophosphate, 6-chloropurine riboside 5'-monophosphate, or N6-methyl-AMP, [14C]AMP was formed from 20 microM [14C]Ado at up to 50% of the rate recorded with 1 mM unlabelled AMP. In the presence of 0.2 mM of the unlabelled analog nucleosides tubercidin, N6-methyladenosine, or 6-methylmercaptopurine riboside, [14C]Ado was generated from 1 mM [14C]AMP at up to 60% of the rate recorded with 0.2 mM unlabeled Ado. Small amounts of [14C]Ado were also formed from the natural nucleosides 5-amino-4-imidazolecarboxamide (AICA) riboside or 2'-deoxyadenosine. Administration of therapeutic anticancer and antiviral nucleosides that can serve as substrates for the exchange reaction catalyzed by adenosine kinase might, thus, result in a net production of Ado, a potent autacoid with physiological effects in numerous tissues.

Adenosine↗

PubMed1993

Synthesis and antileukemic activity of certain D-fucopyranosyl nucleosides.

Based upon previously discovered antileukemic properties of 9-beta-D-fucopyranosyladenine (1) in cell culture, four new nucleosides containing naturally occurring bases have been prepared from D-fucose. alpha-D-Fucopyranose tetraacetate was condensed with the silylated bases in either acetonitrile or 1,2-dichloroethane with tin(IV) chloride as the catalyst. The intermediate blocked nucleosides were obtained in crystalline form and deacetylated with methanolic sodium methoxide. 1-beta-D-Fucopyranosyluracil (8), 1-beta-D-fucopyranosylthymine (9), 1-beta-D-fucopyranosylcytosine (10) as the hydrochloride salt, and 7-beta-D-fucopyranosylguanine (11) were crystallized, and their structures were verified by spectroscopic techniques. Nucleosides 8 and 9 had only borderline activity against leukemia L1210 cells grown in culture, whereas nucleoside 11 had activity equal to 1. However, nucleoside 10 proved to be twice as active as either 1 or 11. The antileukemic activity, which was due to the inhibition of cell division, was reversible by transfer of the arrested cells to fresh media or by the addition of cytidine.

Animals↗

PubMed1990

Purine nucleoside modulation of functions of human lymphocytes.

The accumulation of endogenous substrates in patients with adenosine deaminase deficiency or purine nucleoside phosphorylase deficiency is believed to be responsible for the immunodeficiency observed in these patients. To identify the lymphocyte populations that are most susceptible to these substrates, we investigated the effect of their nucleoside analogs on a number of T and B cell functions of human lymphocytes. We found that tubercidin (Tub), 2-chloro 2'deoxyadenosine (2CldA), 2-fluoro adenine arabinoside-5'phosphate (FaraAMP), and 9-beta-D-arabinosyl guanine (AraGua) inhibited the proliferative responses of human peripheral blood mononuclear cells (PBMC) to polyclonal activators (PHA, OKT3 mab) or to allogeneic PBMC in mixed lymphocyte cultures (MLC). Addition of recombinant IL-2 from the beginning of the culture did not alter the inhibition by Tub of the proliferative responses of PBMC. These purine nucleoside analogs also inhibited the proliferative responses of purified human peripheral blood CD4+ and CD8+ T cells to PHA and of purified B cells to SAC. The concentrations of these nucleosides required to achieve a given degree of inhibition of proliferative responses of T lymphocyte subpopulations or B cells was similar, suggesting that these analogs do not exhibit any selectivity for these purified lymphocyte populations. Tub and FaraAMP, respectively, inhibited and enhanced, at the effector phase, both NK cytotoxicity and specific T cell-mediated cytotoxicity. In contrast to these findings, LAK cytotoxicity at the effector phase was not significantly inhibited by Tub, and was not enhanced by FaraAMP. Both analogs inhibited rIL-2-induced proliferative responses of PBMC, but did not affect the generation of LAK cytotoxicity (induction phase) against the K562 targets when added at the beginning of the culture. This suggests that DNA synthesis is not required for LAK cell induction. Both Tub and FaraAMP inhibited immunoglobulin production (IgG and IgM) by PBMC in the PWM-induced system. These results demonstrate that purine nucleoside analogs significantly inhibited a number of functions of human lymphocytes. Although selectivity for T lymphocyte subpopulations and B cells was not observed, a differential effect of Tub and FaraAMP on LAK cytotoxicity versus NK cytotoxicity and specific T cell cytotoxicity was found.

B-Lymphocytes↗

PubMed1993

Urinary excretion of modified nucleosides as biological marker of RNA turnover in patients with cancer and AIDS.

Using boronate gel affinity chromatography and reversed-phase high-performance liquid chromatography (RP-HPLC), a method for the simultaneous determination of 12 urinary modified nucleosides has been developed. The RP-HPLC fractions were identified by gas chromatography/mass spectrometry analysis. The HPLC quantitation of urinary nucleoside levels before and after surgery of cancer patients suggested that urinary 5'-deoxy-5'-methylthioadenosine and N-[(9-beta-D-ribofuranosyl-9H-purine-6-yl) carbamoyl]-L-threonine (t6A) levels were helpful in monitoring therapeutic effects in cancer patients. From the fact that molar ratios of urinary N2,N2-dimethylguanosine (m2 2G)pseudouridine (psi) and t6A/psi in cancer patients were lower than those of normal or post-surgical cancer patients, the increase of rRNA content in cancer tissues growing rapidly was estimated using the stoichiometric relationship between the ratio of the number of residues of their modified nucleoside in RNAs and the proportion of rRNA to total RNAs in average tissues of whole body. Furthermore, from the estimation of RNA turnover using urinary nucleoside levels, it was found that the half-lives of rRNA rather than tRNA of patients with cancer and those of both RNAs in the case of acquired immunodeficiency syndrome (AIDS) were extremely short compared with those of the normal. Thus, we discovered that the selected urinary modified nucleosides were very useful as a biological marker of whole-body RNA turnover in patients with cancer and AIDS.

Acquired Immunodeficiency Syndrome↗

PubMed1989

Subtypes of nucleoside transport inhibitory sites in heart: a quantitative autoradiographical analysis.

We evaluated the interaction of several nucleoside transport inhibitors and substrates with the binding of [3H]nitrobenzylthioinosine ([3H]NBMPR) to nucleoside transport sites in guinea pig cardiac sections. Using quantitative autoradiography, we determined inhibition constants for inhibition of [3H]NBMPR binding to both coronary endothelial cells and cardiac myocytes. We studied the interactions of NBMPR, nitrobenzylthioguanosine, dipyridamole, dilazep, hexobendine, lidoflazine, mioflazine, soluflazine, adenosine, inosine and uridine for these two cell types. Of the compounds tested in this study, lidoflazine (8.2X) and hexobendine (6.3X) have the greatest selectivity for coronary endothelial cell nucleoside transporters. All other compounds had 3-fold or less selectivity. Therefore, there is evidence of nucleoside transporter subtypes between endothelial cells and myocytes. This heterogeneity of transport inhibitory sites on nucleoside transporters may allow the development of agents to modulate selectively some of the cardiovascular effects of adenosine.

Animals↗

PubMed1993

Nucleoside analogues previously found to be inactive against HIV may be activated by simple chemical phosphorylation.

Nucleoside analogues previously found to be inactive against the human immunodeficiency virus (HIV) may be activated by simple chemical derivatisation. As part of our effort to deliver masked phosphates inside living cells we have discovered that certain phosphate triester derivatives of inactive nucleoside analogues become inhibitors of HIV replication. This discovery underlies the importance of the masked phosphate approach, and has significant implications for the future design of chemotherapeutic nucleoside analogues. If highly modified nucleoside analogues may be active without the intervention of nucleoside kinase enzymes, major advantage may accrue in terms of low toxicity and enhanced selectivity. Moreover, the increased structural freedom may have implications for dealing with the emergence of resistance. The concept herein described as 'kinase bypass' may thus stimulate the discovery of a new generation of antiviral agents.

Antiviral Agents↗

PubMed1990

Nucleoside diphosphate kinase from Xenopus oocytes; partial purification and characterization.

We have identified and partially purified a soluble nucleoside diphosphate kinase (NDP kinase) from Xenopus laevis oocytes. The enzyme preparation can catalyze the transfer of phosphate from ATP to all of the major oxy- and deoxynucleotides. It can also catalyze the transfer of a phosphorothioate group from gamma-S-ATP to an acceptor GDP forming gamma-S-GTP. Like NDP kinases from other sources, the catalytic mechanism appears to involve a phosphoenzyme intermediate which can be isolated. Transfer of phosphate from nucleoside triphosphates to protein is rapid, reaching saturation within 1 min following the addition of nucleoside triphosphates. The transfer of phosphate from phosphoprotein intermediate to nucleoside diphosphates is equally fast. While nucleoside diphosphate kinases are generally thought to require magnesium for activity, both the oocyte enzyme preparation and a commercial bovine liver enzyme preparation are only partially inhibited by short (10 min) exposures to 25 mM EDTA. Both enzyme preparations are, however, further inhibited by long incubations with this metal chelator (2 h, 70% inhibition). Zinc enhances the inhibition of NDP kinase by EDTA, but is ineffective on its own. Rapid phosphorylation in the presence of [gamma-32P]ATP and EDTA could be used to identify the phosphoenzyme intermediate in homogenates of Xenopus oocytes and facilitated its isolation. Sodium dodecyl sulfate polyacrylamide gel electrophoresis coupled with autoradiography indicated the presence of only a single phosphorylated species of Mr 21,500 in supernatants of fresh oocyte homogenates. Partial purification of this protein utilizing salt precipitation, hydrophobic-interaction chromatography and an affinity step with Affi-Gel Blue Sepharose resulted in a 100-fold purification and a 29% overall yield of NDP-kinase activity. Size-exclusion chromatography of the purified preparation yielded two peaks containing enzyme activity. They eluted with apparent molecular weights of 45,000 and 70,000, suggesting a native enzyme that is multimeric or associated with other proteins.

Adenosine Triphosphate↗

PubMed1992

Modified nucleosides in human serum.

Methylated purines and pyrimidines derived from the degradation of transfer ribonucleic acid have been shown to be excreted in abnormal amounts in the urine of patients with cancer. Recent technology developed by Gehrke and Kuo has allowed the separation and quantification of modified nucleosides in serum using reversed-phase high-performance liquid chromatography with diode-array measurement. Serum levels of ten modified nucleosides were measured in 37 normal healthy adults to establish normal values and to correlate activity with age and sex. In addition, serum levels of patients with several malignancies were measured to determine activity in these diseases. Levels of modified nucleosides in normal individuals were consistently reproducible and showed no significant variation among males versus females or with age. Patients with malignant diseases showed consistent elevations and these were highest in patients with more advanced disease. The evidence of no significant differences in the mean levels of modified nucleosides in serum with age or sex in normal adults and elevations in patients with malignancies demonstrate the potential value of modified nucleosides as cancer biomarkers.

Adult↗

PubMed1992

Relationships between the chromatographic retention data and the effects of nucleoside derivatives in highly metastatic 3LL cells.

The effect of 21 nucleoside derivatives on the [3H]-thymidine cellular uptake and on the incorporation into DNA of highly metastatic 3LL (Lewis lung carcinoma) cells has been measured. Hydrophobic and hydrophilic molecular parameters (the adsorption capacity, specific adsorption surface, lipophilicity and specific hydrophobic surface area) have been determined by using thin-layer chromatography. Stepwise linear regression analysis and principal component analysis have been applied in order to reveal the relationships between the molecular parameters and the effect of the nucleoside derivatives on highly metastatic 3LL cells. The first principal component obtained from the measured activity data could be attributed to the change of [3H]-thymidine cellular uptake caused by the nucleoside, while the second principal component could be regarded as the measure of the effect on the DNA incorporation of [3H]-thymidine. The effect of the nucleosides on the [3H]-thymidine uptake could be explained by the specific hydrophobic and adsorption surface area of the nucleoside, on the other hand the effect on the DNA incorporation could be described by the adsorption characteristics (specific hydrophilic surface area and adsorption capacity) of the derivatives.

Animals↗

PubMed2005

Nonenzymatic glycation of DNA nucleosides with reducing sugars.

Reducing sugars can react with the free amino groups of proteins to form a heterogeneous group of compounds known as advanced glycation endproducts (AGEs) or Maillard reaction products. The objective of this investigation was to monitor the nonenzymatic glycation of DNA nucleosides and to characterize the formation of nucleoside AGEs using capillary electrophoresis (CE), high-performance liquid chromatography (HPLC), UV fluorescence spectroscopy, and mass spectrometry. Deoxyguanosine, deoxyadenosine, deoxythymidine, and deoxycytidine were used as the model nucleosides and were incubated over time with glucose, galactose, or glyceraldehyde. Under increasing concentrations and time, deoxyguanosine exhibited the highest rate of glycation with glyceraldehyde. Deoxyadenosine and deoxycytidine exhibited comparable reactivity with glyceraldehyde and no appreciable reactivity with galactose or glucose. No reactivity was observed between deoxythymidine and the sugars. A combination of CE, HPLC, UV fluorescence spectroscopy, and mass spectrometry provided a convenient method for characterizing nucleoside AGEs and for monitoring the physical factors that influence the formation of sugar adducts of DNA nucleosides.

Chromatography, High Pressure Liquid↗

PubMed2004

Novel imidazo[1,2-c]pyrimidine base-modified nucleosides: synthesis and antiviral evaluation.

The preparation of a series of novel 6-(beta-D-ribofuranosyl)-2-alkyl/aryl-6H-imidazo[1,2-c]pyrimidin-5-one nucleosides and the 2-nitrile nucleosides, 6-(beta-D-ribofuranosyl)-5-oxo-5,6-dihydro-imidazo[1,2-c]pyrimidine-2-carbonitrile and 2R and 2S isomers of 6-(beta-D-ribofuranosyl)-5-oxo-2,3,5,6-tetrahydro-imidazo[1,2-c]pyrimidine-2-carbonitrile, is described using two synthetic approaches. The nucleoside mimetics described were evaluated against a wide range of viral types and strains in cell culture. With the exception of one nucleoside, which displayed anti-CMV activity at toxic concentrations, none of the compounds showed antiviral activity most likely due to a lack of substrate recognition by viral and/or cellular nucleoside kinases.

Animals↗

PubMed2006

Synthesis, X-ray crystal structural study, antiviral and cytostatic evaluations of the novel unsaturated acyclic and epoxide nucleoside analogues.

A series of the novel purine and pyrimidine nucleoside analogues were synthesised in which the sugar moiety was replaced by the 4-amino-2-butenyl (2-6 and 10-18) and oxiranyl (8 and 20) spacer. The Z- (2-6) and E-isomers (10-18) of unsaturated acyclic nucleoside analogues were synthesized by condensation of 2- and 6-substituted purine and 5-substituted uracil bases with Z- (1) or E-phthalimide (9) precursors. The oxiranyl nucleoside analogues (8 and 20) were obtained by epoxidation of 1 and 9 with m-chloroperoxybenzoic acid and subsequent coupling with adenine. The new compounds were evaluated for their antiviral and antitumor cell activities. Among the olefinic nucleoside analogues, Z-isomer of adenine containing 4-amino-2-butenyl side chain (6) exhibited the best cytostatic activities, particularly against colon carcinoma (SW 620, IC50 = 26 microM). Its E-isomer 15 did not show any antiproliferative activity against malignant tumor cell lines, except for a slight inhibition of colon carcinoma (SW 620, IC50 = 56.5 microM) cells. In general, Z-isomers showed better cytostatic activities than the corresponding E-isomers. (Z)-4-Amino-2-butenyl-adenine nucleoside analogue 6 showed albeit modest but selective activity against HIV-1 (EC50 = 4.83 microg mL(-1)).

Antineoplastic Agents↗