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Results for “Deoxyadenosines”

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At least 19 recordsLinked to original sources

PubMed2000

Role of the phosphorolysis of deoxyadenosine in the cytotoxic effect of the combination of deoxyadenosine and deoxycoformycin on a human colon carcinoma cell line (LoVo).

In LoVo cells, phosphorolytic activity acting on deoxyadenosine plays a major role in the resistance to the cytotoxic effect of the combination of deoxynucleoside with deoxycoformycin. In fact, the observed dependence of toxicity on cell density appears to be related to the metabolic conversion of deoxyadenosine into adenine. The phosphorylation of the deoxynucleoside, which represents the first step towards the formation of the cytotoxic agent dATP, proceeds at a significantly lower rate as compared to the phosphorolysis of deoxyadenosine. The analysis of the levels of deoxyadenosine and its derivatives in the incubation media reveals that the rates of disappearance of deoxyadenosine and of formation of adenine increase in concert with the reduction of the effect on cell survival.

Antineoplastic Agents↗

PubMed1995

The influence of 2-chloro-2'-deoxyadenosine on metabolism of deoxyadenosine in human primary CNS lymphoma.

The effects of 2-chloro-2'-deoxyadenosine (2CdA) on the activity of enzymes important for the metabolism of deoxyadenosine were studied in lysates prepared from human primary central nervous system (CNS) lymphomas and normal human lymphocytes. Strong inhibition (approximately 100%) of the phosphorylation of deoxyadenosine to its deoxynucleotide phosphate derivatives was produced in both systems in the presence of 2CdA, which was phosphorylated concomitantly to 2-chloro-2'-deoxyAMP. Interestingly, 2CdA was also found to be an inhibitor of the deamination of both deoxyadenosine (over 50%) and AMP (70%). These findings add to our understanding of the mechanisms of toxicity of this drug, especially considering that 2CdA is resistant to deamination by adenosine deaminase. These results challenge the existing theories of 2CdA toxicity, which have been limited to the formation of phosphate derivatives of 2CdA. The present in vitro studies have demonstrated that 2CdA also inhibits both phosphorylation and deamination of deoxyadenosine (dAdo), suggesting that its mechanism of toxicity includes a block in dAdo metabolic pathways. This has important implications for the perturbation of cell methylation, a functionality associated with, for example, apoptosis.

5'-Nucleotidase↗

PubMed1977

Solution conformational analysis of 2'-amino-2''deoxyadenosine, 3'-amino-3'-deoxyadenosine and puromycin by pulsed nuclear-magnetic-resonance methods.

The solution conformation of 2'-amino-2'-deoxyadenosine, 3'-amino-3'-deoxyadenosine, and 3'-amino-3'-deoxy-6-N,N-dimethyladenosine have been determined by nuclear magnetic resonance in aqueous and ammonia solutions. The analysis of the ribose moiety is based on the two-state S in equilibrium N model of Altona and Sundaralingam. Longitudinal proton relaxation time and nuclear Overhauser enchancement measurements have been carried out in order to characterize the orientation of the base relative to the ribose. Those studies indicate that 3'-amino-3'-deoxyadenosine and 3'-amino-3'-deoxy-6-N,N-dimethyladenosine exist in solution preferentially in the N-anti-g + conformations. On the other hand, 2'-amino-2'-deoxyadenosine adopts the S-syn-g +/t conformation families. It appears that the base is restricted to the anti conformation in the first two compounds, while in 2'-amino-2'-deoxyadenosine, one third of the molecules in the S state are in the anti range. These studies corroborate the previously proposed correlations between the N state of the ribose and the anti orientation of the base and between the S state of the ribose and the syn orientation of the base.

Deoxyadenosines↗

PubMed2005

Activation of deoxycytidine kinase by deoxyadenosine: implications in deoxyadenosine-mediated cytotoxicity.

The inborn deficiency of adenosine deaminase is characterised by accumulation of excess amounts of cytotoxic deoxyadenine nucleotides in lymphocytes. Formation of dATP requires phosphorylation of deoxyadenosine by deoxycytidine kinase (dCK), the main nucleoside salvage enzyme in lymphoid cells. Activation of dCK by a number of genotoxic agents including 2-chlorodeoxyadenosine, a deamination-resistant deoxyadenosine analogue, was found previously. Here, we show that deoxyadenosine itself is also a potent activator of dCK if its deamination was prevented by the adenosine deaminase inhibitor deoxycoformycin. In contrast, deoxycytidine was found to prevent stimulation of dCK by various drugs. The activated form of dCK was more resistant to tryptic digestion, indicating that dCK undergoes a substrate-independent conformational change upon activation. Elevated dCK activities were accompanied by decreased pyrimidine nucleotide levels whereas cytotoxic dATP pools were selectively enhanced. dCK activity was found to be downregulated by growth factor and MAP kinase signalling, providing a potential tool to slow the rate of dATP accumulation in adenosine deaminase deficiency.

Adenine Nucleotides↗

PubMed2004

3-nitro-3-deaza-2'-deoxyadenosine as a versatile photocleavable 2'-deoxyadenosine mimic.

A new photocleavable 2'-deoxyadenosine mimic, 3-nitro-3-deaza-2'-deoxyadenosine (NidA), was prepared and introduced into DNA fragments via its 6-O-trimethylphenyl precursor phophoramidite. Photocleavage of the resulting oligonucleotide is highly efficient in single and double strands. Hybridization properties of NidA are very similar to those of deoxyadenosine.

Biomimetic Materials↗

PubMed1986

Effects of cytotoxicity of 2-chloro-2'-deoxyadenosine and 2-bromo-2'-deoxyadenosine on cell growth, clonogenicity, DNA synthesis, and cell cycle kinetics.

The cytotoxic effects of the adenosine deaminase resistant analogues 2-bromo-2'-deoxyadenosine (2-BrdAdo) and 2-chloro-2'-deoxyadenosine (2-CldAdo) have been compared with those of deoxyadenosine (dAdo). Like 2-CldAdo, 2-BrdAdo is highly effective in inhibiting the growth of many T-lymphoblastoid, B-lymphoblastoid, and myeloid cell lines in culture. Concentrations required to inhibit growth of CCRF-CEM human T-lymphoblastoid cells by 50% (IC50) are: 2-CldAdo, 0.045 microM; 2-BrdAdo, 0.068 microM; dAdo, 0.9 microM in the presence of 5 microM erythro-9-(2-hydroxy-3-nonyl)adenine. Like dAdo, 2-BrdAdo causes a much greater decrease in DNA synthesis than in RNA and protein synthesis. For each of the nucleosides the concentration required to cause 50% inhibition of DNA synthesis (as measured by thymidine incorporation) in an 18-h exposure is very similar to the IC50 for growth and to the concentration required to decrease viability (clonogenicity) over 18 h by 50% (EC50). A fraction of CCRF-CEM cells (approximately equal to 30%) is resistant to killing by exposure to 2-BrdAdo or 2-CldAdo for 4 h at concentrations 100 times the EC50, but 3% of cells are resistant to exposure for 4 h to a concentration of dAdo 3 times the EC50. Each of the three nucleosides causes accumulation of cells in S phase, the accumulation becoming more marked with longer periods of exposure and with higher concentrations of nucleoside. During exposures for 18-24 h at a concentration of nucleoside near the EC50 most cells accumulate in S, with most in early S, whereas exposure to concentrations greater than EC95 accumulates cells at the G1/S border. This suggests that loss of viability is associated with a blockade of some process specifically occurring at the initiation of S phase. At an optimum dosage schedule, 2-BrdAdo and 2-CldAdo have similar therapeutic effects against L1210 in vivo, both producing over 99% cell kill, but the optimum dosage of 2-CldAdo is lower.

Animals↗

PubMed1988

Metabolic effects of 3'-deoxyadenosine (cordycepin) and 2-halo-3'-deoxyadenosine on repair of X-ray-induced potentially lethal damage in Chinese hamster V79 cells.

Using cultured Chinese hamster V79 cells, an attempt has been made to examine the phosphorylation of cordycepin and its 2-halo derivatives (2-chloro-3'-deoxyadenosine, 2-bromo-3'-deoxyadenosine, and 2-iodo-3'-deoxyadenosine) by adenosine kinase, within the cells, and to correlate it with their cytotoxicities and abilities to inhibit the repair of X-ray-induced potentially lethal damage (PLDR). Of all compounds, only cordycepin was found to be phosphorylated and showed both potent cytotoxicity and ability to inhibit PLDR.

2-Chloroadenosine↗

PubMed1996

Synthesis and characterization of 8-methoxy-2'- deoxyadenosine-containing oligonucleotides to probe the syn glycosidic conformation of 2'-deoxyadenosine within DNA.

The synthesis of 8-methoxy-2'-deoxyadenosine (moA) protected at N6 as an N,N-dimethylformamidine derivative and incorporation of the modified nucleoside into oligodeoxynucleotides via the phosphoramidite method are described. UV thermal denaturation studies were conducted on duplexes containing moA:G, moA:C and moA:T base pairs to determine the thermodynamic stability of duplexes containing moA relative to their adenosine (A)-containing counterparts. In the case of moA:G base pairs the effect of moA substitution is sequence dependent. In A:G mismatch-containing sequences, which have been shown by structural characterization to have a syn conformational preference at the glycosidic bond of A, moA substitution results in stabilization of the duplex. In contrast, in sequences where the A in the A:G mismatch has been shown to prefer the anti conformation moA substitution is destabilizing to the duplex. Thus moA may be a useful probe for investigating the conformational preferences of the N-glycosidic bond of adenosine within DNA. In addition, moA nucleoside is more resistant to acid-catalyzed depurination than previously described 8-bromo-2'-deoxyadenosine, allowing for facile incorporation into oligonucleotides via automated solid phase DNA synthesis.

Base Sequence↗

PubMed2002

5'-Esters of 2'-deoxyadenosine and 2-chloro-2'-deoxyadenosine with cell differentiation-provoking agents.

Phenylacetic and retinoic acids are carboxyacidic cell differentiating agents displaying anticancer activities. We report on a new class of compounds including the 5'-esters of 2'-deoxyadenosine (dA) or 2-chloro-2'-deoxyadenosine (cladribine, 2CdA) and the aforementioned acids. The rationale behind the synthesis of these esters was that if they are hydrolyzed inside the lymphoid cells, either dA will be removed from the intracellular environment by deamination, or 2CdA will be phosphorylated and accumulated. In either case targetted delivery of the differentiating agent to the lymphoid cells may be envisaged. The said compounds were synthesized by the Mitsunobu procedure employing triphenylphosphine and azadicarboxylic acid esters, and their stability was tested against various esterases. Esters of dA and 2CdA with phenylacetic acids were found to be resistant to enzymatic hydrolysis, whereas those with retinoic acids were efficiently hydrolyzed by commercially available hepatic esterase as well as by esterases present in the blood plasma and in diluted human lymphocyte lysate. Susceptibility to enzymatic hydrolysis was found to be a prerequisite of cytotoxic and/or differentiating activity of these esters in leukemic cell lines.

Antineoplastic Agents↗

PubMedDate not supplied

Kinetics and metabolism of 2-chloro-2'-deoxyadenosine and 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine in the isolated perfused rat liver.

2-Chloro-2'-deoxyadenosine (CdA), a newly developed anticancer drug, has been tested in phase II trials in the treatment of lymphoproliferative disorders. 2-Chloro-2'-arabino-fluoro-2'-deoxyadenosine (CAFdA), an acid stable derivative of CdA with promising anti-lymphoproliferative activity, has been suggested as a potentially effective oral drug. In the present study, we investigated the metabolism of CdA and CAFdA in isolated perfused rat liver. The liver was recycled with a perfusate containing CdA or CAFdA (2-200 micrograms/ml) for 3.5 h. The elimination half-lives were concentration-dependent for both CdA and CAFdA. The elimination rate of CAFdA was slower than that of CdA, suggesting that CAFdA is more stable than CdA against deglycosylation by hepatic enzymes. The amount of 2-chloroadenine (CAde), the major metabolite of CdA and CAFdA, increased proportionally with time and dose. The first passage effect was approximately 50% both for CdA and CAFdA. Less than 1% of CdA and CAFdA were recovered as intact drug in the bile during the experiment and less than 1% of CdA and 0.1% of CAFdA were found as CAde in the bile, respectively. The structural identity of metabolites present in the perfusates was verified utilizing electrospray ionization mass spectrometry.

Adenine Nucleotides↗

PubMed1992

7-Deaza-2'-deoxyadenosine and 3-deaza-2'-deoxyadenosine replacing dA within d(A6)-tracts: differential bending at 3'- and 5'-junctions of d(A6).d(T6) and B-DNA.

7-Deaza-2'-deoxyadenosine (1, c7Ad) and 3-deaza-2'-deoxyadenosine (2, c3Ad) have been incorporated into d(AAAAAA) tracts replacing dA at various positions within oligonucleotides. For this purpose suitably protected phosphonates have been prepared and oligonucleotides were synthesized on solid-phase. The oligomers were hybridized with their cognate strands. The duplexes were phosphorylated at OH-5' by polynucleotide kinase and self-ligated to multimers employing T4 DNA ligase. Oligomerized DNA-fragments were analyzed by polyacrylamide gel electrophoresis and the bending was determined from anomalies of electrophoretic mobility. Replacement of dA by c3Ad decreased the bending more than replacement by c7Ad. Reduction of bending was much stronger when the modified nucleosides replaced one or several dA residues at the 3'-site of an d(AAAAAA)-tract whereas replacement at the 5'-site showed no significant influence [1, 2].

Base Sequence↗

PubMed1997

Stability and analysis of 2-chloro-2'-deoxyadenosine, 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine and 2-chloroadenine in human blood plasma.

Cladribine (2-chloro-2'-deoxyadenosine, CdA) is a purine nucleoside analog with activity against lymphoproliferative and autoimmune disorders. 2-Chloro-2'-arabino-fluoro-2'-deoxyadenosine (CAFdA), a derivative of CdA with better acid stability, shows a similar in vitro spectrum of activity as CdA. 2-Chloroadenine (CAde) is the major catabolite of both CdA and CAFdA. We have developed a high performance liquid chromatography method to measure CdA, CAFdA and their metabolite CAde in plasma. This method employees an internal standard, chloroadenosine (CAdo), and a C8 solid-phase extraction to isolate and concentrate the substances. Chromatographic separation was achieved using a C8 reverse-phase column, with UV detection at 265 nm, which gives a limit of detection of 1 nmol/l for all substances. The method was reproducible with intra- and inter-assay coefficients of variations below 6% at 50 nmol/l and at 5 nmol/l below 23%. The average recoveries of CdA, CAde, CAFdA and the internal standard were higher than 70%. Stability studies of authentic patient samples show that samples containing CdA should be kept in a refrigerator or on ice to prevent degradation. Plasma containing CAde should not be kept at -20 degrees C for longer than 10 weeks before analysis. CdA and CAFdA remain almost stable during storage at -20 degrees C for 12 weeks.

Adenine↗

PubMed1998

Unusual nucleoside triphosphate donors for nucleoside kinases: 3'-deoxyadenosine-2'-triphosphate and 2'-deoxyadenosine-3'-triphosphate.

Two non-conventional analogues of ATP, 3'-deoxyadenosine-2'-triphosphate (3'-d-2'-ATP) and 2'-deoxyadenosine-3'-triphosphate (2'-d-3'-ATP), the syntheses of which are described, were examined as potential phosphate donors for the nucleoside kinases: 2'-deoxycytidine kinase (dCK), cytosolic thymidine kinase (TK1) and mitochondrial thymidine kinase (TK2). The reactions were monitored by means of a mixture of [gamma-32P]ATP and cold analogue, and/or with the use of 3H-labelled acceptors and cold donor. With dCK, using equimolar mixtures of ATP with each analogue, and dC as acceptor, phosphate transfer from 3'-d-2'-ATP and 2'-d-3'-ATP amounted to 34% and 14%, respectively. With each analogue used alone (each at concentration of 100 microM), phosphate transfer from 3'-d-2'-ATP was 55% that from ATP, and from 2'-d-3'-ATP 16%. With human TK2, and equimolar mixtures of [gamma-32P]ATP with each of the analogues, and 1 microM dT as acceptor, there was no detectable transfer from either analogue. But, when each analogue was used alone, phosphate transfer attained 11% and 5%, respectively, that for ATP alone. With the low affinity form of human TK1, and dT as acceptor, only low phosphate transfer occurred with either analogue used alone. Both compounds exhibited Michaelis-Menten kinetics (with significantly lower Vmax than ATP), while ATP exhibited cooperative kinetics with all three kinases.

Catalysis↗

PubMed1999

Distribution of 2-chloro-2'-deoxyadenosine, 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine, fludarabine and cytarabine in mice: a whole-body autoradiography study.

The distribution characteristics of tritiated nucleoside analogs, 2-chloro-2'-deoxyadeonosine (CdA), 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine (CAFdA), 2-fluoroarabinosyladenine (F-ara-A) and cytosine arabinoside (ara-C) were compared in mice using whole-body autoradiography. CdA, CAFdA and F-ara-A have quite similar molecular structures, but they differ substantially in clinical activity as well as the side effects. Eight mice were injected intravenously in couples. One mouse from each pair was killed 20 min postinjection and the other mouse from each pair 4 h after the injection. The distribution of the label was then analyzed by whole-body autoradiography. The distribution of the nucleoside analogs was rapid and uniform. High concentrations were found in highly perfused organs. After 4 h the overall concentration had decreased but relatively high activities were found in the skin for CdA and CAFdA, in the thymus for ara-C and the bone marrow for CdA. Both CdA and CAFdA were found in the brain, but the concentration was surprisingly lower after 4 h for CAFdA, a lipophilic and more stable analog as compared to CdA. There was an uptake of CdA, F-ara-A and CAFdA in the skin. There were signs of retention of ara-C in parts of the thymus. The present investigations indicate that the nucleoside analog transport to the brain in mice is not primarily dependent upon passive diffusion over a lipophilic barrier, but suggestive of a specific transport mechanism.

Adenine Nucleotides↗

PubMed1971