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PubMed1989

Extraction of intracellular nucleosides and nucleotides with acetonitrile.

Extraction of intracellular nucleosides and nucleotides with acetonitrile (ACN) and water was compared with extraction with 60 g/L perchloric acid (PCA), followed by neutralization with KOH, 1 mol/L. Freshly isolated rat bone-marrow and intestinal cells were incubated with radiolabeled 5-fluorouracil (FUra) and 5-fluorodeoxyuridine. The ribose and deoxyribose nucleosides and nucleotides of FUra, and ADP and ATP in the soluble extracts were separated by HPLC and measured by scintillation counting or ultraviolet absorbance. The insoluble precipitates were digested in 1 mol/L NaOH and analyzed for the radioactive macromolecule-bound nucleotides. Both extraction methods yielded the same total (i.e., soluble and insoluble) amount of radioactivity. However, the ACN method yielded significantly more FUra nucleosides and triphosphate nucleotides and ATP in the soluble fraction, and more proteins and macromolecule-bound nucleotides in the insoluble fraction. In the PCA method, the soluble fraction contained more monophosphate nucleotides and ADP than in the ACN method. The PCA extraction procedure promoted decomposition of ATP to ADP and interfered with the ion-pairing reversed-phase HPLC assay. The ACN extraction is faster (less than 5 min) than the PCA extraction (greater than 10 min). Moreover, the ACN in the soluble extract fraction can be removed by evaporation and thus does not interfere with the HPLC analysis. Thus the ACN method evidently is suitable for extraction of nucleosides and nucleotides.

Acetonitriles↗
PubMed2003

A review of HIV-1 resistance to the nucleoside and nucleotide inhibitors.

The nucleoside reverse transcriptase inhibitors (NRTIs) were the first class of agents used for the treatment of HIV and remain an important component of combination antiretroviral therapy. Resistance to the NRTIs occurs by the acquisition of mutations in the reverse transcriptase gene that result in a structural change that either decreases the NRTI incorporation into the extending nucleotide chain or enhances removal of the NRTI from the terminated chain, also known as primer unblocking or pyrophosphorylysis. There are several major genetic mutational patterns of resistance and cross-resistance that evolve with the NRTIs including the thymidine analog mutations M41L, D67N, K70R, L210W, T215Y, and K219Q/E/W, the non-thymidine mutations M184V, L74V, and K65R, and the multidrug resistant Q151M complex, as well as others. Increasing knowledge of resistance and cross-resistance patterns that evolve on the NRTIs as well as the other antiretroviral classes will help optimize antiretroviral treatment strategies. Advancing knowledge of the biochemical and structural basis of resistance will aid in the design of newer compounds that are active against HIV resistant to the currently available drugs, ultimately prolonging virologic suppression and life in the millions of people who are infected with HIV.

Drug Resistance, Viral↗
PubMed1995

Profile of nucleotides and nucleosides of human milk.

The content of nucleotides and nucleosides of human milk was analyzed using a newly developed method for high performance liquid chromatography. By this method it is possible to analyze nucleotides and nucleosides simultaneously. Human milk was pooled according to season, lactation period, and geographical area. Three kinds of nucleosides--cytidine, uridine, and adenosine--and 6 kinds of nucleotides--5'-CMP, 5'-UMP, 5'-AMP, 5'-GMP, 5'-IMP, and 5'-CDP--were detected. Cytidine, 5'-CMP, and 5'-CDP predominated throughout lactation. Also there seemed to be geographical differences in nucleoside composition. The overall amounts of nucleotides and nucleosides were higher in winter than in summer. No nucleosides were detected in bovine milk, nor in bovine milk-based infant formula, and bovine milk contained much less nucleotides than human milk. These results suggest that nucleosides and nucleotides found in human milk may play some important roles in the development of infants.

Adenosine↗
PubMed1999

Dietary nucleosides and nucleotides reduce Cryptosporidium parvum infection in dexamethasone immunosuppressed adult mice.

Numerous studies have demonstrated that dietary sources of nucleosides and nucleotides are important for the maintenance of cellular and humoral immune responses. To determine the immunological effects of feeding a nucleoside-nucleotide mixture to dexamethasone-immunosuppressed C57BL/6 adult mice infected with Cryptosporidium parvum, we examined fecal oocyst shedding, lymphoproliferative responses to concanavalin (Con) A, and C. parvum antigen, interleukin (IL-2), and gamma-interferon (IFN-gamma) production by cultured spleen cells. Mice were fed a nucleotide-free 20% casein diet (control group) or this diet supplemented with a 0. 5% nucleoside-nucleotide mixture before and after inoculation with C. parvum. Spleens from mice receiving the supplemented diet had higher (P < 0.05) Con A and antigen-specific induced cell proliferation than those from control mice. In addition to the increased cell proliferation, the spleen cells from the supplemented mice produced significantly more IL-2 (P < 0.002) and significantly more IFN-gamma (P <; 0.004) than cells from the control mice. Mice fed the supplemented diet excreted fewer (P < 0.05) C. parvum oocysts in the feces than control mice. The cumulative survival rate in the nucleoside-nucleotide mixture-fed group was higher compared with the control group (P < 0.05). We conclude that nucleosides and nucleotides may partially counteract the immunosuppressive effects of dexamethasone in C. parvum-challenged mice.

Animals↗
PubMed1987

Inhibition of human purine nucleoside phosphorylase by acyclic nucleosides and nucleotides.

In an effort to develop more potent inhibitors of human purine nucleoside phosphorylase (PNP) as immunosuppressive and cancer chemotherapeutic agents, the affinity of the erythrocytic enzyme for 30 acyclic nucleosides, nucleotides and related compounds was determined. Among the acyclonucleosides, 2'-nordeoxyguanosine [2'NDG, 9-(1,3-dihydroxy-2-propoxymethyl)guanine] had a 3-fold greater affinity than acyclovir, and 8-amino-2'NDG was the best inhibitor with Ki = 2.6 X 10(-7) M. The ether moiety of the acyclovir and 2'NDG side-chains was not important for binding. Phosphorylated 2'NDG analogs appeared to act as multisubstrate analogs with optimal binding at low (1 mM) phosphate concentration. The 2'NDG mono- and triphosphates had higher affinities than those reported for the phosphorylated acyclovir derivatives but the diphosphate had a similar Ki value of 9 X 10(-9) M. Poor affinity, independent of phosphate concentration, was found for 9-(2-phosphonoethyl)guanine. The 3'-phosphate derivative of 8-(3-hydroxypropyl)-9-methylguanine inhibited with a Ki = 2 X 10(-5) M in 1 mM phosphate. The chemical syntheses of new analogs are described.

Acyclovir↗
PubMed1998

Nucleotide and nucleoside analogues as inhibitors of cytosolic 5'-nucleotidase I from heart.

Substrate and product specificity studies were used to develop inhibitors of the cytosolic 5'-nucleotidase I (c-N-I) from myocardium. As measured by Vmax/Km, c-N-I preferred pyrimidine 2'-deoxyribonucleotides as substrates with thymidine monophosphate (TMP) being the most efficient. In product inhibition studies, thymidine inhibited noncompetitively and inorganic phosphate inhibited competitively, consistent with an ordered release of nucleoside prior to phosphate. Mirroring nucleotide substrate specificities, pyrimidine nucleosides were more potent product inhibitors than purine nucleosides. Thus, pyrimidine nucleotide and nucleoside analogues were developed as inhibitors. Phosphonate analogues of TMP were synthesized by a novel method. The most potent was the 5'-phosphonate of 3'-deoxythymidine (ddT) (apparent Ki value of 63 nM). In addition, pyrimidine nucleoside analogues were inhibitors with 5-ethynyl-2',3'-dideoxyuridine being the most potent (apparent Ki value of 3.7 microM). The most potent nucleotide and nucleoside inhibitor were both greater than 1000-fold more potent inhibiting c-N-I than the cytosolic 5'-nucleotidase II. The nucleoside analogue was also greater than 1000-fold more potent against c-N-I than the membrane ecto-5'-nucleotidase (e-N). Because the phosphonate analogues measurably inhibited e-N (apparent Ki values of 6-12 microM), the selectivity of the phosphonates for c-N-I versus e-N was less (40-200-fold). Because of the high selectivity for c-N-I versus both of the other 5'-nucleotidases, the nucleoside inhibitors of c-N-I may be useful biochemical tools in discerning the role that c-N-I plays in generating adenosine within myocardium.

5'-Nucleotidase↗
PubMed1993

Limitation of stunning in dog myocardium by nucleoside and nucleotide mixture, OG-VI.

BACKGROUND: OG-VI is a nucleoside-nucleotide solution composed of 30 mM inosine, 30 mM cytidine, 30 mM sodium 5'-guanylate, 22.5 mM uridine, and 7.4 mM thymidine. It is expected to enhance the efficacy of intravenous hyperalimentation in surgically stressed patients. One of the main causes of ischemic myocardial damage is loss of adenine nucleotides from heart cells. The aim of the present study, therefore, was to examine the effect of OG-VI on myocardial mechanical function and energy metabolism in stunned myocardium. METHODS: Pentobarbital-anesthetized dogs were subjected to 20 min ligation of the left anterior descending (LAD) coronary artery, followed by reperfusion for 30 min. OG-VI at 0.1 or 0.2 ml/kg/min or saline was infused from the left femoral vein throughout the experiment. The tissue levels of high-energy phosphates in the hearts were determined after 30 min reperfusion. RESULTS: LAD flow, first derivative of left ventricular pressure (LVdp/dt), and segment function were increased by OG-VI in a dose-dependent manner. OG-VI infusion resulted in a significant improvement in LVdP/dt and segment shortening in the ischemic/reperfused myocardium compared with saline infusion. The levels of segment shortening with saline, 0.1, and 0.2 ml/kg/min OG-VI after reperfusion for 30 min were -0.3, 75, and 82% of the preligation levels, respectively. The tissue level of adenosine triphosphate (ATP) after reperfusion in OG-VI-infused animals was significantly higher than that in saline-infused animals. CONCLUSION: OG-VI has a positive inotropic action, and its infusion results in a marked cardioprotective effect in stunned myocardium associated with the restoration of tissue ATP level.

Animals↗
PubMed1999

Selective hydrolysis of nucleotides to nucleosides and free bases.

The kinetics of the hydrolysis of 2'-deoxyadenosine-5'-monophosphoric acid (dAMP), 2'-deoxycytidine-5'-monophosphoric acid (dCMP), 2'-deoxyguanosine-5'-monophosphoric acid (dGMP) and tymidine-5'-monophosphoric acid (dTMP) was studied in the presence of Xanthomonas maltophilia [1]. The reaction products are nucleosides: 2'-deoxyadenosine (dA), 2'-deoxycytidine (dC), 2'-deoxyguanosine (dG) and tymidine (dT), respectively, or the respective free bases. Hydrolysis of dTMP and dGMP proceeded stepwise according to the sequence: nucleotide-->nucleoside-->free base, whereas no accumulation of the free base was observed during the hydrolysis of dAMP and dCMP.

Hydrolysis↗
PubMed2003

Homo- and heteroexchange of adenine nucleotides and nucleosides in rat hippocampal slices by the nucleoside transport system.

(1) Here, we investigated how nucleotides and nucleosides affect the release of tritiated purines and endogenous adenosine 5'-triphosphate (ATP) from superfused rat hippocampal slices. (2) ATP elicited concentration-dependent [(3)H]purine efflux from slices preloaded with [(3)H]adenosine. High-performance liquid chromatography analysis of the effluent showed that the tritium label represented the whole set of adenine nucleotides and nucleosides, and ATP significantly increased the outflow of [(3)H]ATP. (3) Adenosine 5'-diphosphate, adenosine, uridine, uridine 5'-triphosphate, alpha,beta-methylene-ATP and 3'-O-(4-benzoylbenzoyl)-ATP were also active in eliciting [(3)H]purine release. Adenosine (300 micro M) also evoked endogenous ATP efflux from the hippocampal slices. (4) Reverse transcription-coupled-polymerase chain reaction analysis revealed that mRNAs encoding a variety of P2X and P2Y receptor proteins are expressed in the rat hippocampus. Nevertheless, neither P2 receptor (i.e. pyridoxal-5-phosphate-6-azophenyl-2',4'-disulphonic acid, 30 micro M, suramin, 300 micro M and reactive blue 2, 10 micro M), nor adenosine receptor (8-cyclopentyl-1,3-dipropylxanthine, 250 nM and dimethyl-1-propargylxanthine, 250 nM) antagonists modified the effect of ATP (300 micro M) to evoke [(3)H]purine release. (5) The nucleoside transport inhibitors, dipyridamole (10 micro M), nitrobenzylthioinosine (10 micro M) and adenosine deaminase (2-10 U ml(-1)), but not the ecto-adenylate kinase inhibitor diadenosine pentaphosphate (200 micro M) significantly reduced ATP-evoked [(3)H]purine efflux. (6) In summary, we found that ATP and other nucleotides and nucleosides promote the release of one another and themselves by the nucleoside transport system. This action could have relevance during physiological and pathological elevation of extracellular purine levels high enough to reverse the nucleoside transporter.

Adenine Nucleotides↗
PubMed1982

[Inhibition of luciferase from the firefly Luciola mingrelica by ATP analogs].

The effects of the ATP analogs--nucleotide bases, nucleosides, nucleotide 5'-mono, 5'-di- and 5'-triphosphates -- on the bioluminescence of luciferin oxidation in the presence of firefly (Luciola mingrelica) luciferase were studied. It was shown that all the compounds tested are luciferase inhibitors, differing in terms of inhibition mechanisms. The inhibition by all the ATP analogs is non-competitive with respect to luciferin, the Ki values varying from 0.3 to 56 mM. With respect to ATP the nucleotide bases, nucleosides and 5'-diphosphates are non-competitive inhibitors, whereas nucleotide 5'-mono- and 5'-triphosphates are inhibitors of the mixed type. The Ki values vary from 0.02 to 220 mM, depending on the inhibitor structure. The non-competitive inhibition is influenced by binding two inhibitor molecules to an enzyme molecule. An allosteric mechanism of luciferase inhibition by ATP analogs is proposed and possible functioning of the ATP-binding site on the enzyme is discussed.

Adenosine Triphosphate↗
PubMed2000

Interaction between NiCl2, and nucleobases, nucleosides and nucleotides.

The interaction between NiCl, and nucleobases, nucleosides and nucleotides has been studied by UV-Vis difference spectrophotometry, graphite furnace atomic absorption spectrophotometry, IR spectroscopy and high pressure liquid chromatography using the technique of continuous variation. The proposed structures of the complexes formed were optimised and their electronic and vibrational spectra generated using the molecular modelling program HyperChem 5. Ni2+ reacts with guanine, 2'-dGMP, GMP, adenine and AMP to form 1:1 complexes Ni(Guanine)(H2O)5, Ni(2'-dGMP)(H2O)5, Ni(GMP)(H2O)5, Ni(Adenine)(H2O)5, and Ni(AMP)(H2O)5 respectively. In these complexes, Ni2+ is believed to be bonded to the N7 atom of adenine and guanine.

Guanine↗
PubMed1986

Synthesis and biological activity of certain nucleoside and nucleotide derivatives of pyrazofurin.

A number of nucleoside and nucleotide derivatives of 4-hydroxy-3-beta-D-ribofuranosylpyrazole-5-carboxamide (pyrazofurin, 1) were prepared and tested for their antiviral and cytostatic activity in cell culture. Treatment of 1 with benzyl bromide gave 4-O-benzylpyrazofurin (4). Methylation of 4 with CH2N2 and subsequent removal of the benzyl group by catalytic hydrogenation provided 1-methylpyrazofurin (8). Direct methylation of 1 with CH3I furnished 4-O-methylpyrazofurin (6). Dehydration of the pentaacetylpyrazofurin (9) with phosgene furnished 4-acetoxy-3-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-1-acetylpyrazol e-5-carbonitrile (10). A similar dehydration of the precursor tetraacetyl derivative of 4 gave the corresponding carbonitrile, which on deprotection and subsequent treatment with hydroxylamine furnished 4- (benzyloxy)-3-beta-D-ribofuranosylpyrazole-5-carboxamidoxime (13). Treatment of the tetraacetyl derivative of 4 with Lawesson's reagent and subsequent deacetylation furnished a mixture of 4- (benzyloxy)-3-beta-D-ribofuranosylpyrazole-5-thiocarboxamide (15) and the corresponding nitrile derivative (16). Phosphorylation of unprotected 4 with POCl3 and subsequent debenzylation of the intermediate 17 gave pyrazofurin 5'-phosphate (18), which provided the first chemical synthesis of 18. Similar phosphorylation of 4 with POCl3 and quenching the reaction mixture with either EtOH or MeOH, followed by debenzylation, furnished the 5'-O-(ethyl phosphate) (19b) and 5'-O-(dimethyl phosphate) (20b) derivatives of pyrazofurin. DCC-mediated cyclization of 17, followed by debenzylation, gave pyrazofurin 3',5'-(cyclic)phosphate (21b). The NAD analogue 23b was also prepared by the treatment of 17 with an activated form of AMP in the presence of AgNO3. The structural assignment of 7,8, and 20a were made by single-crystal X-ray analysis, and along with pyrazofurin, their intramolecular hydrogen bond characteristics have been studied. All of these compounds were tested in Vero cell cultures against a spectrum of viruses. Compounds 18 and 23b were active at concentrations very similar to pyrazofurin but are less toxic to the cells than pyrazofurin. Compounds 19b, 20b, and the 3',5'-(cyclic)phosphate 21b are less active than 1. Compounds 18, 19b, 20b, and 23b also exhibited significant inhibitory effects on the growth of L1210 and P388 leukemias and Lewis lung carcinoma cells in vitro, whereas B16 melanoma cells were less sensitive to growth inhibition by these compounds. Pyrazofurin derivatives modified at the 1-, 4-, or 5-position showed neither antiviral nor cytostatic activity in cell culture.

Amides↗
PubMed1997

Role of nucleosides and nucleotides in the immune system, gut reparation after injury, and brain function.

Emerging evidence indicates the importance of nucleosides and nucleotides in the maintenance of functions of the bone marrow hematopoietic cells, intestinal mucosa, and the brain, which have limited de novo synthesis of purine and pyrimidine bases. We have found that nucleosides and nucleotides stimulate hemopoieses and increase peripheral neutrophil counts in mice treated with cyclophosphoamide. Intraperitoneal administration of nucleosides and nucleotides decreased bacterial translocation, the number of colony-forming units, and increased survival against methicillin-resistant Staphylococcus aureus. In vitro immune studies in mice showed that nucleosides and nucleotides increase the delayed-type cutaneous hypersensitivity and the popliteal lymph node blastogenic response to antigens, allogens, and mitogens. Both intraperitoneal and oral administration of nucleosides and nucleotides reduced endotoxin-induced bacterial translocation and improved injury to the gut in protein-deficient mice. However, oral administration of nucleosides and nucleotides in experimental colitis resulted in a worsening of colitic conditions and increased interleukin-8 and tumor necrosis factor-alpha concentrations in inflamed colonic portions, indicating the pro-inflammatory activities of nucleosides and nucleotides. Memory-deficient senescence-accelerated mice and mice with dementia showed improved memory with dietary nucleosides and nucleotides supplementation. These results indicate that supplementation with nucleosides and nucleotides is beneficial to the functions of the system and the brain. However, beneficial effects to the gut appear to depend on the type of damage sustained by the gut.

Animals↗
PubMed1967

Oxidation of pyrimidine nucleosides and nucleotides by osmium tetroxide.

1. Pyrimidine nucleosides such as thymidine, uridine or cytidine are oxidized readily at 0 degrees by osmium tetroxide in ammonium chloride buffer. There is virtually no oxidation in bicarbonate buffer of similar pH. Oxidation of 1-methyluracil yields 5,6-dihydro-4,5,6-trihydroxy-1-methyl-2-pyrimidone. 2. Osmium tetroxide and ammonia react reversibly in aqueous solution to form a yellow 1:1 complex, probably OsO(3)NH. A second molecule of ammonia must be involved in the oxidation of UMP since the rate of this reaction is approximately proportional to the square of the concentration of unprotonated ammonia. 3. 4-Thiouridine reacts with osmium tetroxide much more rapidly than does uridine. The changes of absorption spectra are different in sodium bicarbonate buffer and in ammonium chloride buffer. They occur faster in the latter buffer and, under suitable conditions, cytidine is a major product. 4. Polyuridylic acid is oxidized readily by ammoniacal osmium tetroxide, but its oxidation is inhibited by polyadenylic acid. Pyrimidines of yeast amino acid-transfer RNA are oxidized more slowly than the corresponding mononucleosides, especially the thymine residues. Appreciable oxidation can occur without change of sedimentation coefficient.

Chromatography↗