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At least 19 recordsLinked to original sources
PubMed1985

Metabolic basis of arabinonucleoside selectivity for human leukemic T- and B-lymphoblasts.

Purine analogues are potentially useful agents for selective chemotherapy of lymphoproliferative diseases. We compared the toxic effects of various arabinonucleosides against eight human T- and B-lymphoblastoid lines. The arabinosides of cytosine (ara-C), 2-fluoroadenine (F-ara-A), adenine (ara-A) and guanine (ara-G) all inhibited the growth of T-lymphoblasts at concentrations below 2 microM. Only ara-G showed strong selectivity for T-cells, as indicated by a 15- to 250-fold greater toxicity toward T-cell lines than B-cell lines. To investigate the biochemical basis for ara-G selectivity, we compared the metabolism of the arabinonucleosides in CCRF-CEM (T-) versus PF-2S (B-) lymphoblasts. Comparison of arabinonucleoside triphosphate accumulation indicated differences favoring selective ara-GTP formation in T-cells. In contrast, ara-C, ara-A, and F-ara-A formed almost corresponding amounts of their triphosphates in both cell types. Triphosphate accumulation correlated directly with inhibition of DNA synthesis in CCRF-CEM and PF-2S cells. PF-2S cells accumulated less than 20% ara-GTP from the nucleoside than did CCRF-CEM cells. Nucleoside kinase measurements showed no significant differences in arabinonucleoside phosphorylation that could account for the preferential ara-GTP accumulation in T-cells. After removal of arabinonucleoside-containing medium, ara-GTP levels in PF-2S cells declined with a half-life of 49 min whereas, in CCRF-CEM cells, the level of analogue triphosphate remained unchanged. Furthermore, the half-life of ara-CTP, ara-ATP, and F-ara-ATP in the B-cells was 3- to 5-fold longer than that of ara-GTP. These results indicate that ara-G is more selective than other known arabinonucleosides; such selectivity warrants further assessment of the therapeutic potential of this agent against T-cell malignancies and other lymphoid disorders.

Arabinofuranosylcytosine Triphosphate↗
PubMed1985

Metabolism and selectivity of arabinonucleoside in human lymphoid cells.

The selective toxicity of purine deoxynucleosides against lymphoid cells appears to be mediated by a preferential accumulation of the corresponding triphosphates in these cells. We report a study of the metabolism and toxicity of arabinonucleosides of guanine and cytosine toward human T- and B-lymphoblastoid-cell lines. Both compounds inhibited the growth of T lymphoblasts at concentrations less than 2 microM. However, only ara-G exhibited a strong selectivity for T lymphocytes as indicated by a 100-fold greater toxicity to T than B cells. ara-G is not significantly degraded to guanine but is metabolized to the triphosphate. In common with the other arabinonucleoside, cytotoxicity by ara-G was associated with specific inhibition of DNA synthesis in cells. The capacity of T cells (CCRF-CEM) to accumulate ara-GTP was dependent primarily on deoxycytidine kinase. The level of intracellular ara-GTP accumulated after incubation with the corresponding nucleoside was 20- to 40-fold higher in T cells than either of two B-lymphoblast-cell lines, WI-L2 or PF-2S. The levels of phosphorylating activity for ara-C in extracts of T- and B-cell lines were approximately equal; in contrast, ara-G phosphorylating activity was four- to fivefold higher in B lymphoblasts. After removal of arabinonucleosides from the culture medium, ara-GTP levels in B lymphoblasts declined at a rate that was two to four times faster than that of ara-CTP. In marked contrast, no catabolism of the arabinonucleoside triphosphates was detected in T lymphoblasts. These results suggest that the selectivity of arabinonucleosides to human lymphoid cells of various phenotypes can be correlated with their nucleotide metabolism. The selectivity of ara-G for T and B cells can be correlated with their differential ability to catabolize ara-GTP.

Arabinonucleosides↗
PubMed1979

Correlations of conformational parameters and equilibrium conformational states in a variety of beta-D-arabinonucleosides and their analogues.

H nuclear magnetic resonance spectroscopy has been applied to a study of the conformations of a variety of purine and pyrimidine beta-D-arabinofuranosyl nucleosides. The experimental results, together with data collected from the literature, demonstrated the existence of reasonably good correlations between the coupling constants made it possible to define more accurately, than hitherto possible, the conformational states between which equilibria exist in solution. The equilibrium for the arabinonucleosides differs from that previously established for ribonucleosides; in particular, structural modifications and solvent effects may appreciably modify the conformational states between which equilibria exist. Preliminary measurements on some arabinosides in the syn conformation about the glycosidic bond indicated that these do not conform to the foregoing correlations, and will require separate study. A correlation has also been established between the conformation of the arabinose ring and that of the exocyclic 5'-CH2OH group. For both purine and pyrimidine arabinonucleosides, the conformational state 3E of the arabinose ring coexists to some extent with a gauche-gauche conformation of the exocyclic 5'-CH2OH, as in the case of pyrimidine (but not purine) ribonucleosides. Application of the foregoing to some biological problems is described.

Arabinonucleosides↗
PubMed2003

3-Bromopyrazolo[3,4-d]pyrimidine 2'-deoxy-2'-fluoro-beta-D-arabinonucleosides: modified DNA constituents with an unusually rigid sugar N-conformation.

The nucleobase anion glycosylation of 3-bromo-4-isopropoxy-1H-pyrazolo[3,4-d]pyrimidin-6-amine (6) with 3,5-di-O-benzoyl-2-deoxy-2-fluoro-alpha-d-arabinofuranosyl bromide (5) furnished the protected N(1)-beta-d-nucleosides 7 (60%) and 8 (ca. 2%) along with the N(2)-beta-d-regioisomer 9 (9%). Debenzoylation of compounds 7 and 9 yielded the nucleosides 10 (81%) and 11 (76%). Compound 10 was transformed to the 2'-deoxyguanosine derivative 1 [6-amino-3-bromo-1-(2-deoxy-2-fluoro-beta-d-arabinofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4-one] (85% yield) and the purine-2,6-diamine analogue 2 [3-bromo-1-(2-deoxy-2-fluoro-beta-d-arabinofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4, 6-diamine] (78%). Both nucleosides form more than 98% N-conformer population (P(N) ca. 358 degrees and psi(m) ca. 37 degrees ) in aqueous solution. Single-crystal X-ray analysis of 1 showed that the sugar moiety displays also the N-conformation [P = 347.3 degrees and psi(m) = 34.4 degrees ] in the solid state. The remarkable rigid N-conformation of the pyrazolo[3,4-d]pyrimidine 2'-deoxy-2'-fluoro-beta-d-arabinonucleosides 1 and 2 observed in solution is different from that of the parent purine 2'-deoxy-2'-fluoro-beta-d-arabinonucleosides 3 and 4, which are in equilibrium showing almost equal distribution of the N/S-conformers.

Arabinonucleosides↗
PubMed1995

A facile synthesis of 4'-thio-arabinonucleosides as potential antiviral agents from D-glucose.

As potential antiviral agents, 4'-thio-arabinonucleosides were synthesized. Methyl 3-O-benzyl-xylo-furanoside, readily obtained from D-glucose, was converted to 1,4-anhydro-4-deoxy-4-thio-arabinitol. The protection of hydroxyl groups and the Pummerer rearrangement, followed by Lewis acid induced glycosylation afforded 4'-thio-arabinonucleosides. The compounds showed anti HSV-1 activity.

Antiviral Agents↗
PubMed1996

Glyceraldehyde-3-phosphate dehydrogenase antisense oligodeoxynucleotides protect against cytosine arabinonucleoside-induced apoptosis in cultured cerebellar neurons.

Cytosine arabinonucleoside (AraC) is a pyrimidine antimetabolite that kills proliferating cells by inhibiting DNA synthesis and, importantly, is also an inducer of apoptosis. We recently reported that age-induced apoptotic cell death of cultured cerebellar neurons is directly associated with an over-expression of a particulate 38-kDa protein, identified by us as glyceraldehyde-3-phosphate dehydrogenase (GAPDH; EC 1.2.1.12). We now show that the AraC-induced neuronal death of immature cerebellar granule cells in culture is effectively delayed by actinomycin-D, cycloheximide, or aurintricarboxylic acid (a DNase inhibitor). Furthermore, two GAPDH antisense, but not their corresponding sense, oligodeoxyribonucleotides markedly arrested AraC-induced apoptosis. This protection was more effective than that induced by the above-mentioned classical inhibitors of apoptosis. Prior to AraC-induced neuronal death, GAPDH mRNA levels increased by approximately 2.5-fold, and this mRNA accumulation was blocked by actinomycin-D and the GAPDH antisense (but not sense) oligonucleotide. Like actinomycin-D, a GAPDH antisense oligonucleotide also suppressed the AraC-induced over-expression of the 38-kDa particulate protein (i.e., GAPDH), while the corresponding sense oligonucleotide was totally ineffective. Thus, the present results show that GAPDH over-expression is involved in AraC-induced apoptosis of cultured cerebellar granule cells.

Animals↗
PubMed2000

2'-Deoxy-2'-fluoro-beta-D-arabinonucleosides and oligonucleotides (2'F-ANA): synthesis and physicochemical studies.

Recently, hybrids of RNA and D-arabinonucleic acids (ANA) as well as the 2'-deoxy-2'-fluoro-D-arabinonucleic acid analog (2'F-ANA) were shown to be substrates of RNase H. This enzyme is believed to be involved in the primary mechanism by which antisense oligonucleotides cause a reduction in target RNA levels in vivo. To gain a better understanding of the properties of arabinose based oligonucleotides, we have prepared a series of 2'F-ANA sequences of homopolymeric (A and T) and mixed base composition (A, T, G and C). UV thermal melting and circular dichroic (CD) studies were used to ascertain the thermodynamic stability and helical conformation of 2'F-ANA/RNA and 2'F-ANA/DNA hybrids. It is shown that 2'F-ANA has enhanced RNA affinity relative to that of DNA and phosphorothioate DNA. The 2'-fluoroarabino modification showed favorable pairing to single-stranded DNA also. This is in sharp contrast to ANA, which forms weak ANA/DNA hybrids at best. According to the measured thermodynamic parameters for duplex formation, the increased stability of hybrids formed by 2'F-ANA (e.g., 2'F-ANA/RNA) appears to originate from conformational pre-organization of the fluorinated sugars and a favorable enthalpy of hybridization. In addition, NMR spectroscopy revealed a five-bond coupling between the 2'F and the base protons (H6/H8) of 2'-deoxy-2'-fluoro-beta-D-arabinonucleosides. This observation is suggestive of a through-space interaction between 2'F and H6/H8 atoms. CD experiments indicate that 2'F-ANA/RNA hybrids adopt an 'A-like' structure and show more resemblance to DNA/RNA hybrids than to the pure RNA/RNA duplex. This feature is believed to be an important factor in the mechanism that allows RNase H to discriminate between 2'F-ANA/RNA (or DNA/RNA) and RNA/RNA duplexes.

Arabinose↗
PubMedDate not supplied

Spectrophotometric determination of the pK values for dissociation of the sugar hydroxyls in pyrimidine arabinonucleosides.

Spectrophotometric titration in the ultraviolet has been employed to determine the pK values for dissociation of the sugar hydroxyls in pyrimidine arabinonucleosides and some of their O'-methyl and O'-ethyl derivatives. The order of dissociation of the sugar hydroxyls in the arabinofuranose ring was 2'-OH greater than 3'-OH greater than 5'-OH. The higher acidity (lower pK) of the 2'-OH was interpreted in terms of formation of an intramolecular hydrogen bond of the form 5'-OH....2'-O(--) and the accompanying changes in conformation of the arabinose ring. The various factors affecting the dissociation of specific hydroxyls in some of the O'-alkyl derivatives are discussed in relation to steric, conformational and other effects.

Arabinofuranosyluracil↗
PubMed1989

Immunospecific targeting of cytosine arabinonucleoside-containing liposomes to the idiotype on the surface of a murine B-cell tumor in vitro and in vivo.

A new tumor model is described that is suitable for the evaluation of antibody-directed drug-delivery protocols and a modification in the procedure for covalently coupling antibody to the surface of drug-containing liposomes is presented. These immunospecific liposomes containing cytosine arabinonucleoside (Ara-C) have been tested in vitro and in vivo for their ability to kill a B-cell tumor. The target of the immunospecific-Ara-C liposomes is the idiotype associated with an antigen-specific immunoglobulin receptor on the cell surface of a murine B-cell hybrid (2C3). Affinity-purified antibodies specific for the idiotype were covalently coupled to modified lipid on the surface of the large unilamelar liposomes containing drug. These liposomes were shown to kill idiotype-positive 2C3 cells in vitro, but not idiotype-negative variants of this same cell line. It was also established in vitro that the drug-containing liposomes were at least 40 times more efficient than free Ara-C in the killing of the tumor cells. The 2C3 tumor was also propagated in vivo following the i.p. administration of tumor cells. The tumor grew initially as multiple foci within the peritoneum and subsequently spread to the spleen. Tumor-bearing mice were treated either with free Ara-C or with immunospecific liposomes containing Ara-C. Tumor growth in the primary tumor nodules and in the spleen was monitored by the administration of bromodeoxyuridine to the tumor-bearing animals followed by the immunofluorescent staining of cells with a monoclonal anti-bromodeoxyuridine antibody to estimate the proportion of cells in S phase. Our data from five out of seven animal experiments shows that the immunospecific-Ara-C liposomes, but not free drug, reduced tumor growth in the spleen. However, neither the liposomes containing drug nor the free drug were able to alter the growth of the primary tumor nodules growing in the peritoneal cavity. These results suggest that immunospecific-Ara-C containing liposomes may be useful in conjunction with other cytoreductive protocols in controlling tumor growth or preventing the spread of the tumor to other sites, but that immunospecific-Ara-C containing liposomes by themselves are not likely to eliminate an established tumor in vivo. We also demonstrate here that the administration of immunospecific-Ara-C containing liposomes in an animal having high levels of circulating tumor-associated antigen (i.e., IgG containing the idiotype) represents a potential clinically relevant hazard which must be considered when designing antibody-directed drug-delivery protocols.

Animals↗
PubMed1979

Conformational analysis of arabinonucleosides and nucleotides. A comparison with the ribonucleosides and nucleotides.

Conformations of arabino nucleosides and nucleotides have been analyzed by semiempirical energy calculations. It is found that the change in the configuration of the O(2')-hydroxyl group in arabinoses compared to riboses exerts significant influence on the conformational priorities of the glycosyl and the exocyclic C(4')-C(5') bond torsions. While the anti conformations for the bases are preferred, the anti in equilibrium or formed from syn interconversion is considerably hampered compared to ribosides due to large energy barrier. Further the preferred anti glycosyl torsions are shifted to higher values for C(3')-endo puckers and in ribosides. While the gauche+ conformation around the C(4')-C(5') bond is favored for C(3')-endo arabinosides, it is strongly stabilized for C(2')-endo arabinosides only in the presence of the intrasugar hydrogen bond O(2')-H ... O(5'). The net attractive electrostatic interactions between the phosphate and the base stabilizes the preferred conformations of 5'-arabinonucleotides also.

Arabinonucleosides↗
PubMed2002

Oligonucleotides comprised of alternating 2'-deoxy-2'-fluoro-beta-D-arabinonucleosides and D-2'-deoxyribonucleosides (2'F-ANA/DNA 'altimers') induce efficient RNA cleavage mediated by RNase H.

Chimeric oligonucleotides comprised of alternating residues of 2'-deoxy-2'-fluoro-D-arabinonucleic acid (2'F-ANA) and DNA were synthesized and evaluated for an important antisense property-the ability to elicit ribonuclease H (RNase H) degradation of complementary RNA. Experiments used both human RNase HII and Escherichia coli RNase HI. Mixed backbone oligomers comprising alternating three-nucleotide segments of 2'F-ANA and three-nucleotide segments of DNA were the most efficient at eliciting RNase H degradation of target RNA, and were significantly better than oligonucleotides entirely composed of DNA, suggesting that these mixed backbone oligonucleotides may be potent antisense agents.

Arabinonucleosides↗
PubMed1990

Synthesis and cytotoxicity studies of 8-amino-6-methyl-2-beta-D-ribofuranosyl-1,2,3,5,6,7-hexaazaacenaphthyle ne (7-aza-TCN) and the corresponding 2'-deoxy- and arabinonucleoside analogues.

The tricyclic nucleoside 8-amino-6-N-methyl-2-beta-D-ribofuranosyl-1,2,3,5,6, 7-hexaazaacenaphthylene was synthesized from 8-amino-6-N-methyl-4-(methylthio)-2-beta-D-ribofuranosyl-1,2,3,5,6, 7-hexaazaacenaphthylene. The 2'-deoxy analogue of 5, 8-amino-6-N-methyl-2-(2-deoxy-beta-D-ribofuranosyl)-1,2,3,5,6, 7-hexaazaacenaphthylene (11), and the arabino analogue of (5), 8-amino-6-N-methyl-2-beta-D-arabinofuranosyl-1,2,3,5,6, 7-hexaazaacenaphthylene (14) were synthesized from 5. Nucleosides 2,3,4,5,11, and 14 were evaluated for potential anticancer activity by measuring their ability to inhibit the growth of L1210 and H. Ep. 2 tumor cells in vitro.

Acenaphthenes↗
PubMed2000

Stereocontrolled syntheses of deoxyribonucleosides via photoinduced electron-transfer deoxygenation of benzoyl-protected ribo- and arabinonucleosides.

The stereocontrolled, de novo syntheses of beta-2'-deoxy-, alpha-2'-deoxy-, beta-3'-deoxy-, and beta-2', 3'-dideoxyribonucleosides are described. Strategically protected ribose, arabinose, and xylose glycosylation precursors were synthesized bearing C2-esters capable of directing Vorbrüggen glycosylation. The key step is the regioselective deoxygenation of the desired hydroxyl group as either the benzoyl- or 3-(trifluoromethyl)benzoyl derivative. This deoxygenation is accomplished via a photoinduced electron-transfer (PET) mechanism using carbazole derivatives as the photosensitizer. The syntheses of the desired deoxynucleoside generally proceed in three steps from a common, readily available precursor.

Arabinonucleosides↗
PubMed2003

2'-Spiro ribo- and arabinonucleosides: synthesis, molecular modelling and incorporation into oligodeoxynucleotides.

We have synthesized four conformationally restricted bicyclic 2'-spiro nucleosides via 2'-C-allyl nucleosides as key intermediates. The ribo-configured 2'-spironucleosides 9b and 14b were obtained by a convergent strategy starting from 2-ketofuranose 1 whereas the arabino-configured 2'-spironucleosides 21 and 27 were obtained by a linear strategy with a 2'-ketouridine derivative as starting material. The furanose ring of 9b/14b adopts N-type conformations whereas the furanose ring of 21/27 exists as an N<==>S equilibrium. These compounds showed no anti-HIV-1 activity or cytotoxicity. Incorporation of the four 2'-spironucleosides (as monomers X4 and X5) into oligodeoxynucleotides was accomplished using the phosphoramidite approach on an automated DNA synthesizer. Irrespective of monomeric configuration, hybridization studies revealed that these 2'-spironucleotide monomers (X4 and X5) induce decreased duplex thermostabilities compared with the corresponding DNA:DNA and DNA:RNA duplexes. Molecular modelling indicated that steric constraints are a possible reason for the lowered binding affinities of the modified oligodeoxynucleotides towards complementary single-stranded DNA and single-stranded RNA complements.

Anti-HIV Agents↗
PubMed2004

Halogenated 7-deazapurine nucleosides: stereoselective synthesis and conformation of 2'-deoxy-2'-fluoro-beta-D-arabinonucleosides.

The stereoselective syntheses of 5-halogenated 7-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine nucleosides 3b-d, 4a-c as well as 7-deaza-2'-deoxyisoguanosine are described. Nucleobase anion glycosylation of 2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5) with 3,5-di-O-benzoyl-2-deoxy-2-fluoro-alpha-D-arabinofuranosyl bromide (6) exclusively gave the beta-D-anomer, which was deblocked (--> 8), aminated at C4 (--> 3a) and selectively deaminated at C2 to yield 2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl 7-deazaisoguanine (2). Condensation of the 5-halogenated 4-chloro-2-pivaloylamino-7H-pyrrolo[2,3-d]pyrimidines 9a-c with 6 furnished the N7-nucleosides 10a-c together with N2,N7-bisglycosylated compounds 11a-c. The former was converted to the corresponding 2,4-diamino-compounds 3b-d, and the latter was deblocked by NaOMe/MeOH to yield the 4-methoxy-nucleosides 4a-c. Conformational analysis of the sugar moiety of the nucleosides 2 and 3a-d was performed on the basis of vicinal [1H,1H] coupling constants. The fluorine atom in the sugar moiety shifts the sugar conformation from S towards N by about 10%, while the halogen substituents in the base moiety increase the hydrophobicity and polarizability of the nucleobases.

Arabinonucleosides↗
PubMedDate not supplied

Effect of substituting arabinonucleosides for deoxynucleotides in the DNA priming strand on the polymerase action of HIV-1 RT.

The ability of 5'-DNA-araN-3' chimeras to serve as primers during HIV-1 RT-catalyzed DNA synthesis was assessed. It is shown that while the structural changes imparted by the arabinose units are minimal, the biological outcome is significant. For example, a DNA strand with arabinocytidine (araC) at the 3'-terminus was found to serve as a primer of DNA synthesis but significant pausing of HIV-RT was observed after the addition of 4 dNTP's. This phenomenon was not observed for the analogous DNA primer containing a riboC unit or an all-DNA strand.

Arabinonucleosides↗
PubMedDate not supplied

Synthesis of 2'-spiro ribo- and arabinonucleosides.

Four conformationally restricted bicyclic 2'-spiro nucleosides were synthesised and incorporated into oligonucleotides. These spiro nucleotides induced decreased duplex thermostabilities.

Arabinonucleosides↗