Nucleosides containing arabinose as their sugar moiety.

Base pairing of anhydrohexitol nucleosides with 2,6-diaminopurine, 5-methylcytosine and uracil asbase moiety. (1/176)

Hexitol nucleic acids (HNAs) with modified bases (5-methylcytosine, 2,6-diaminopurine or uracil) were synthesized. The introduction of the 5-methylcytosine base demonstrates that N -benzoylated 5-methylcytosyl-hexitol occurs as the imino tautomer. The base pairing systems (G:CMe, U:D, T:D and U:A) obey Watson-Crick rules. Substituting hT for hU, hCMefor hC and hD for hA generally leads to increased duplex stability. In a single case, replacement of hC by hCMedid not result in duplex stabilization. This sequence-specific effect could be explained by the geometry of the model duplex used for carrying out the thermal stability study. Generally, polypurine HNA sequences give more stable duplexes with their RNA complement than polypyrimidine HNA sequences. This observation supports the hypothesis that, besides changes in stacking pattern, the difference in conformational stress between purine and pyrimidine nucleosides may contribute to duplex stability. Introduction of hCMeand hD in HNA sequences further increases the potential of HNA to function as a steric blocking agent.  (+info)

Comparison of the mechanism of cytotoxicity of 2-chloro-9-(2-deoxy-2- fluoro-beta-D-arabinofuranosyl)adenine, 2-chloro-9-(2-deoxy-2-fluoro- beta-D-ribofuranosyl)adenine, and 2-chloro-9-(2-deoxy-2,2-difluoro- beta-D-ribofuranosyl)adenine in CEM cells. (2/176)

In an effort to understand biochemical features that are important to the selective antitumor activity of 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)adenine [Cl-F( upward arrow)-dAdo], we evaluated the biochemical pharmacology of three structurally similar compounds that have quite different antitumor activities. Cl-F( upward arrow)-dAdo was 50-fold more potent as an inhibitor of CEM cell growth than were either 2-chloro-9-(2-deoxy-2-fluoro-beta-D-ribofuranosyl)adenine [Cl-F( downward arrow)-dAdo] or 2-chloro-9-(2-deoxy-2, 2-difluoro-beta-D-ribofuranosyl)adenine [Cl-diF( upward arrow downward arrow)-dAdo]. The compounds were similar as substrates of deoxycytidine kinase. Similar amounts of their respective triphosphates accumulated in CEM cells, and the rate of disappearance of these metabolites was also similar. Cl-F( upward arrow)-dAdo was 10- to 30-fold more potent in its ability to inhibit the incorporation of cytidine into deoxycytidine nucleotides than either Cl-F( downward arrow)-dAdo or Cl-diF( upward arrow downward arrow)-dAdo, respectively, which indicated that ribonucleotide reductase was differentially inhibited by these three compounds. Thus, the differences in the cytotoxicity of these agents toward CEM cells were not related to quantitative differences in the phosphorylation of these agents to active forms but can mostly be accounted for by differences in the inhibition of ribonucleotide reductase activity. Furthermore, the inhibition of RNA and protein synthesis by Cl-F( downward arrow)-dAdo and Cl-diF( upward arrow downward arrow)-dAdo at concentrations similar to those required for the inhibition of DNA synthesis can help explain the poor antitumor selectivity of these two agents because all cells require RNA and protein synthesis.  (+info)

Oligonucleotide-peptide conjugates as potential antisense agents. (3/176)

Oligonucleotide-peptide conjugates have several applications, including their potential use as improved antisense agents for interfering with the RNA function within cells. In order to provide robust and generally applicable conjugation chemistry, we developed a novel approach of fragment coupling of pre-synthesized peptides to the 2'-position of a selected nucleotide within an otherwise protected oligonucleotide chain attached to a solid support.  (+info)

Biochemical pharmacology and resistance to 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine, a novel analogue of cladribine in human leukemic cells. (4/176)

The objective of the present study was to investigate the biochemical pharmacology of 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine (CAFdA)--a fluorinated analogue of cladribine [2-chloro-2'-deoxyadenosine, Leustatin (CdA)] with improved acid and metabolic stability--in human leukemic cell lines and in mononuclear cells isolated from patients with chronic lymphocytic leukemia (CLL) and acute myelocytic leukemia (AML). We have also made and characterized two cell lines that are not sensitive to the growth inhibitory and cytotoxic effects of CAFdA. Incubation of cells isolated from the blood of CLL and AML patients with various concentrations of CdA or of CAFdA accumulated CdA and CAFdA nucleotides in a dose-dependent manner. A significantly higher rate of phosphorylation to monophosphates was observed for CAFdA than for CdA in cells from CLL patients (n = 14; P = 0.04). The differences in the phosphorylation were even more pronounced for the respective triphosphates in both CLL (n = 14; P = 0.001) and AML (n = 4; P = 0.04) cells. Retention of CAFdA 5'-triphosphate (CAFdATP) was also longer than that for CdA 5'-triphosphate (CdATP) in cells from leukemic patients. The relative efficacy of CAFdA as a substrate for purified recombinant deoxycytidine kinase (dCK), the key enzyme in the activation of nucleoside analogues, was very high and exceeded that of CdA as well as the natural substrate, deoxycytidine, by a factor of 2 and 8, respectively. The Km for CAFdA with dCK was also lower than that for CdA, as measured in crude extracts from the human acute lymphoblastic leukemia cell line CCRF-CEM and the promyelocytic leukemia cell line HL60. Acquired resistance to CAFdA in HL60 and in CCRF-CEM cell lines was directly correlated to the decreased activity of the nucleoside phosphorylating enzyme, dCK. Resistant cells also showed a considerable degree of cross-resistance to analogues that were activated by dCK. These observations demonstrated that dCK phosphorylates CAFdA more efficiently than CdA. Furthermore, CAFdATP is apparently more stable than CdATP and the mechanisms of resistance to CAFdA are similar to those leading to CdA resistance. These results encourage studies on the clinical effect of CAFdA in lymphoproliferative diseases.  (+info)

Arabinosylguanine-induced apoptosis of T-lymphoblastic cells: incorporation into DNA is a necessary step. (5/176)

9-Beta-D-Arabinosylguanine (ara-G) is a recently introduced and effective treatment for T-cell acute lymphoblastic leukemia, but how ara-G and ara-G triphosphate (ara-GTP) kill cells is not known. We hypothesized that, in cycling T-lymphoblastoid cells, ara-G may act directly by incorporation into DNA, which may lead to apoptosis. Hence, blocking the incorporation of ara-G monophosphate (ara-GMP) into DNA may prevent apoptosis. To test this hypothesis, we performed experiments in a T-lymphoblastic leukemia cell line (CCRF-CEM) after synchronization with a double aphidicolin block. Intracellular accumulation of ara-GTP was neither cell cycle dependent nor affected by aphidicolin (53 +/- 5 microM/h without aphidicolin, 50 +/- 5 microM/h with aphidicolin). Cells at the G1-S boundary accumulated 75 +/- 7 microM ara-GTP with minimal incorporation into DNA (5 +/- 2 pmol ara-GMP/mg DNA) and had little biochemical or morphological evidence of apoptosis. In marked contrast, cells in S phase had significantly more ara-G incorporated into DNA (24 +/- 4 pmol ara-GMP/mg DNA), although the cytosolic concentration of ara-GTP (85 +/- 7 microM) was similar to that in the G1-enriched population. In the S-phase cells, there was a corresponding increase in apoptosis (measured as high molecular weight DNA fragmentation and morphological changes), and the incorporation of ara-GTP into DNA resulted in a >95% inhibition of DNA synthesis. There was a direct linear relationship between the number of cells in S phase and both the total number of ara-GMP molecules in DNA and the inhibition of DNA synthesis. Blocking of ara-GTP incorporation into S-phase DNA abolished biochemical and morphological features of apoptosis, even in the presence of cytotoxic level of intracellular ara-GTP. Taken together, these data demonstrate that the incorporation of ara-GTP into DNA is the critical event that mediates the induction of apoptosis in CCRF-CEM cells.  (+info)

Pharmacokinetics of nelarabine and 9-beta-D-arabinofuranosyl guanine in pediatric and adult patients during a phase I study of nelarabine for the treatment of refractory hematologic malignancies. (6/176)

PURPOSE: To characterize the pharmacokinetics of nelarabine (506U78), the water-soluble prodrug of 9-beta-D-arabinofuranosyl guanine (ara-G), and ara-G in pediatric and adult patients with refractory hematologic malignancies. Ara-G is phosphorylated within leukemic cells to form ara-G triphosphate (ara-GTP), which acts to terminate DNA chain elongation, resulting in cell death. PATIENTS AND METHODS: The pharmacokinetics of nelarabine and/or ara-G were evaluated in 71 patients (25 pediatric and 46 adult patients) on the first day of therapy. Blood was collected at specified times for the determination of plasma nelarabine and ara-G concentrations. RESULTS: There were no statistically significant differences in the pharmacokinetics of nelarabine between any of the groups of patients. The harmonic mean half-life (t1/2) of nelarabine in pediatric and adult patients was 14.1 minutes and 16.5 minutes, respectively. The maximum concentrations (C(max)) of ara-G occurred at or near the end of the nelarabine infusion. The C(max) of ara-G ranged from 11.6 micromol/L to 308.7 micromol/L at nelarabine doses of 5 to 75 mg/kg and was linearly related to the nelarabine dose. No statistically significant differences were noted for the pharmacokinetic parameter estimates of ara-G between adult male and female patients. In children versus adults, the dose-normalized C(max), time of the C(max), and the steady-state volume of distribution of ara-G were similar. However, the clearance of ara-G was higher in pediatric patients (0.312 L.h(-1).kg(-1)) as compared with adult patients (0. 213 L.h(-1).kg(-1)) (P <.001). The t1/2 of ara-G was shorter in pediatric patients as compared with adult patients (2.1 hours v 3.0 hours; P <.01). CONCLUSION: Nelarabine is an effective prodrug of ara-G, allowing systemic concentrations of ara-G that result in clinical activity.  (+info)

Differential incorporation of 1-beta-D-arabinofuranosylcytosine and 9-beta-D-arabinofuranosylguanine into nuclear and mitochondrial DNA. (7/176)

The anti-leukemic nucleoside analogs 1-beta-D-arabinofuranosylcytosine (araC) and 9-beta-D-arabinofuranosylguanine (araG) are dependent on intracellular phosphorylation for pharmacological activity. AraC is efficiently phosphorylated by deoxycytidine kinase (dCK). Although araG is phosphorylated by dCK in vitro, it is a preferred substrate of mitochondrial deoxyguanosine kinase. We have used autoradiography to show that araC was incorporated into nuclear DNA in Molt-4 and CEM T-lymphoblastoid cells as well as in Chinese hamster ovary cells. In contrast, araG was predominantly incorporated into mitochondrial DNA in the investigated cell lines, without detectable incorporation into nuclear DNA. These data suggest that the molecular targets of araG and araC may differ.  (+info)

Retroviral transduction of cancer cell lines with the gene encoding Drosophila melanogaster multisubstrate deoxyribonucleoside kinase. (8/176)

Nucleoside kinases from several species are investigated as "suicide genes" for treatment of malignant tumors by combined gene/chemotherapy. We have recently cloned a multisubstrate deoxyribonucleoside kinase of Drosophila melanogaster (Dm-dNK), and we have shown that the enzyme phosphorylates cytotoxic pyrimidine and purine nucleoside analogs. The broad substrate specificity of the enzyme, as well as its very high catalytic rate, makes it a unique member of the nucleoside kinase enzyme family. In the present study, we evaluated Dm-dNK as a suicide gene by constructing a replication-deficient retroviral vector that expresses the enzyme. The human pancreatic adenocarcinoma cell line MIA PaCa-2 and a thymidine kinase-deficient osteosarcoma cell line were transduced with the recombinant virus. We showed that Dm-dNK can be expressed in human cells, that the enzyme retained its enzymatic activity, and that it is localized in the cell nuclei due to a nuclear localization signal in its C-terminal region. The cells expressing Dm-dNK exhibited increased sensitivity to several cytotoxic nucleoside analogs, such as 1-beta-d-arabinofuranosylcytosine, 1-beta-d-arabinofuranosylthymine, (E)-5-(2-bromovinyl)-2'-deoxyuridine, 2-chloro-2'-deoxyadenosine, and 2',2'-difluorodeoxycytidine. These findings suggest that Dm-dNK may be used as a suicide gene in combined gene/chemotherapy of cancer.  (+info)

Arabinonucleosides are glycosylamines derived from arabinose, a monosaccharide (simple sugar) that is a component of certain complex carbohydrates. In an arabinonucleoside, the arabinose molecule is linked to a nitrogenous base, such as adenine, guanine, cytosine, uracil, or thymine, through a glycosidic bond. These types of compounds are not typically found in nature but can be synthesized in the laboratory for research purposes. They may have potential applications in the development of new drugs, particularly in the area of antiviral and anticancer therapy.

"Arabinonucleosides" is a descriptor in the National Library of Medicines controlled vocabulary thesaurus, MeSH (Medical ... This graph shows the total number of publications written about "Arabinonucleosides" by people in this website by year, and ... Below are the most recent publications written about "Arabinonucleosides" by people in Profiles. ... whether "Arabinonucleosides" was a major or minor topic of these publications. To see the data from this visualization as text ...
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Arabinonucleosides,N0000007990, Calcium Phosphates,N0000007989, Hydroxycholecalciferols,N0000007988, Metalloproteases, ...
Synthesis of the sulfonamido derivatives of arabinonucleosides. 1985, Vol. 50, Issue 2, pp. 383-392 [Abstract] ...
Arabinonucleosides Preferred Term Term UI T003306. Date01/01/1999. LexicalTag NON. ThesaurusID NLM (1979). ... Arabinonucleosides Preferred Concept UI. M0001642. Registry Number. 0. Scope Note. Nucleosides containing arabinose as their ... Arabinonucleosides. Tree Number(s). D13.570.065. Unique ID. D001087. RDF Unique Identifier. http://id.nlm.nih.gov/mesh/D001087 ...
Arabinonucleosides Preferred Term Term UI T003306. Date01/01/1999. LexicalTag NON. ThesaurusID NLM (1979). ... Arabinonucleosides Preferred Concept UI. M0001642. Registry Number. 0. Scope Note. Nucleosides containing arabinose as their ... Arabinonucleosides. Tree Number(s). D13.570.065. Unique ID. D001087. RDF Unique Identifier. http://id.nlm.nih.gov/mesh/D001087 ...
Sugar-modified derivatives of cytostatic 6-(het)aryl-7-deazapurine nucleosides: 2′-C-methylribonucleosides, arabinonucleosides ...
Arabinonucleosides - Preferred Concept UI. M0001642. Scope note. Nucleosides containing arabinose as their sugar moiety. ...
Arabinonucleosides and 2-Deoxyribonucleosides. Naus, P., P. Perlikova, A. Bourderioux, R. Pohl, L. Slavetinska, I. Votruba, G ...
Product Code MR-2002 CAS Number N/A MW 579.98 Formula C10H14N2Na3O16P3 Appearance Clear colorless solution Storage -20℃, Always avoid freeze-thaw cycles. Purity HPLC ≥99%
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Synthesis and Anticancer and Antiviral Activities of C-2-Branched Arabinonucleosides. Bege, Miklós; Kiss, Alexandra; Bereczki ...
Arabinonucleosides Arabinonucleotides Arabinose Arabis Arabs AraC Transcription Factor Araceae Arachidonate 12-Lipoxygenase ...
World Arabia Arabidopsis Arabidopsis Proteins Arabinofuranosylcytosine Triphosphate Arabinofuranosyluracil Arabinonucleosides ...
  • Arabinonucleosides" is a descriptor in the National Library of Medicine's controlled vocabulary thesaurus, MeSH (Medical Subject Headings) . (wakehealth.edu)

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