PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Dideoxynucleosides”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 145 records · Page 8Linked to original sources
PubMed1992

Comparison of the in vitro toxicity of 2',3'-dideoxynucleosides to murine hematopoietic progenitor cells.

Four nucleoside analogues, 2',3'-dideoxyinosine (ddI), 2',3'-dideoxyadenosine (ddA), 2',3'-dideoxycytosine (ddC) and 5-fluoro-2',3'-dideoxycytosine (5-F-ddC), were evaluated for their potential in vitro myelotoxic effects on normal murine hematopoietic progenitor cells. Myeloid granulocyte-macrophage colony-forming units (CFU-gm), erythroid burst-forming units (BFU-e) and colony-forming units (CFU-e) and megakaryocytic (CFU-meg) progenitors were exposed to the agents for 1 h prior to culture in Petri dish assays or continuously throughout the entire culture period. At 10 microM, both ddA and ddI were moderately toxic (2-36% colony inhibition) to murine CFU-gm, BFU-e, CFU-e and CFU-meg following either 1 h or continuous exposure. Colony inhibition for the progenitors ranged from 2-31% at 10 microM for 1 h ddC or 5-F-ddC exposure. Continuous exposure to ddC was highly myelotoxic to murine hematopoietic progenitors with 100 microM suppressing colony formation 82-89%. At the same concentration and exposure time, 5-F-ddC inhibited colony formation 56-67%. Our results demonstrate that 1 h and continuous exposures to ddA and ddI were similarly myelotoxic to murine hematopoietic cells regardless of exposure time. In contrast, continuous ddC or 5-F-ddC exposure was more toxic to murine progenitors than 1 h exposure to these agents.

Animals↗
PubMed1991

The 5'-triphosphates of 3'-azido-3'-deoxythymidine and 2', 3'-dideoxynucleosides inhibit DNA polymerase gamma by different mechanisms.

Inhibition mechanisms of 5'-triphosphates of 3'-azido-3'-deoxythymidine (AZT-TP) and 3'-deoxythymidine (ddTTP) on extensively purified DNA polymerase gamma from bovine testes were examined by analysis of the products synthesized on singly primed M13 single-stranded DNA or synthetic oligonucleotide template-primer in the presence of analogues. The results indicate that AZT-TP inhibits DNA polymerase gamma in competition with dTTP but is not incorporated into DNA, whereas ddTTP is incorporated into DNA and causes chain termination. In contrast, both analogues were used by reverse transcriptase and caused chain termination.

Animals↗
PubMed1991

Na(+)-dependent, concentrative nucleoside transport in rat macrophages. Specificity for natural nucleosides and nucleoside analogs, including dideoxynucleosides, and comparison of nucleoside transport in rat, mouse and human macrophages.

The effects of natural nucleosides and various analogs thereof on Na(+)-dependent, concentrative transport of formycin B by cultured rat macrophages were investigated. Concentrative transport is the sole nucleoside transport system of these cells. The results indicated that uridine, 5'-fluorouridine, all natural purine nucleosides, 2-chloroadenosine and 5'-deoxyadenosine are efficient substrates for the transporter. None of nine other pyrimidine nucleosides was transported. 3'-Deoxy-adenosine, 2',3'-dideoxyadenosine, 8-azidoadenosine, tubercidin, 5'-methylthioadenosine 6-mercaptopurine riboside and adenosine arabinoside were either poor substrates or not transported significantly. The substrate activity of some of the natural nucleosides and the lack of substrate activity of 3'-deoxyadenosine, 2',3'-dideoxyadenosine, 8-azidoadenosine and 2',3'-dideoxycytidine were confirmed by direct uptake measurements. No significant concentrative nucleoside transport was detected in cultured human monocytes/macrophages, whereas mouse macrophages possessed both concentrative and equilibrative nucleoside transporters.

Animals↗
PubMed1995

Intracellular metabolism of 2',3'-dideoxynucleosides in duck hepatocyte primary cultures.

The intracellular fate of the potent duck hepatitis B virus (DHBV) inhibitor 2,6-diaminopurine 2',3'-dideoxyriboside (ddDAPR), its deamination product 2',3'-dideoxyguanosine (ddG), and the less effective DHBV-inhibitor 2',3'-dideoxycytidine (ddC) was investigated in duck hepatocyte primary cultures. After a 1-min exposure of [3H]ddDAPR to duck blood, 95% of the compound was converted to ddG. Similarly, [3H]ddDAPR was converted rapidly to ddG in duck hepatocyte primary cultures, with ddG exhibiting resistance to further catabolism. The major pathway of ddG utilization in these cells was phosphorylation, yielding a concentration of 2.1 and 1.9 microM total ddG nucleotides after 5 and 26 hr, respectively, of exposure to 4 microM ddG. Removal of exogenous ddG led to a rapid (T1/2 = 1.6 hr) decrease in the total intracellular ddG nucleotide pools. Duck hepatocytes treated with 4 microM ddC exhibited a time-dependent accumulation of ddC nucleotides, culminating in a maximum intracellular total ddC nucleotide concentration of 1.4 microM after 24-26 hr. The intracellular total ddC nucleotide level decreased with a T1/2 of 4.4 hr following the removal of exogenous ddC. The formation of ddC nucleotides was reduced in the presence of excess 2'-dideoxycytidine implicating deoxycytidine kinase in the initial step of ddC phosphorylation. A 25-fold excess of 2'-deoxycytidine had no effect on ddG phosphorylation in duck hepatocytes. However, a 92% inhibition of ddG nucleotide formation occurred in duck hepatocytes treated for 5 hr with 4 microM [3H]dG + 100 microM adenosine in the presence of the adenosine deaminase inhibitor 2'-deoxycoformycin, suggesting that, in these cells, adenosine kinase is involved in the ddG phosphorylation process.

Animals↗
PubMed1990

2'-Azido-2',3'-dideoxythymidine: synthesis and crystal structure of a 2'-substituted dideoxynucleoside.

1-(2-Azido-2,3-dideoxy-beta-D-erythro-pentofuranosyl)thymine (2'-N3ddThd) was synthesized from 1-(5-O-trityl-2,3-anhydro-beta-D-lyxofuranosyl)thymine by two different procedures. Method A prepared the title compound by opening of the oxirane ring with LiEt3BH followed by mesylation of the 2'-hydroxyl function, introduction of the 2'-azido substituent and deblocking of the 5'-function. In method B nucleophilic opening of 3'-deoxy-5'-O-(tert-butyldimethylsilyl)-5-methyl-2,2'-anhydrouridine+ ++ was carried out with sodium azide in hexamethylphosphoramide in the presence of benzoic acid. Single X-ray crystallographic studies indicated a solid state conformation (3T2), which was opposite to that of the A form of AZT (2T3) but closely resembled that of 1-(2-fluoro-2,3-dideoxy-beta-D-erythropentofuranosyl)thymine (2'-FddThd) (3T2) and of 3'-azido-2',3'-dideoxy-2,6-diaminopurine riboside (3'-N3ddDAP) (3T2). Whereas the latter displayed significant inhibitory activity against human immunodeficiency virus (HIV) replication, 2'-FddThd and 2'-N3ddThd were essentially inactive.

Antiviral Agents↗
PubMed1996

Zidovudine and dideoxynucleosides deplete wild-type mitochondrial DNA levels and increase deleted mitochondrial DNA levels in cultured Kearns-Sayre syndrome fibroblasts.

Kearns-Sayre syndrome is the most commonly diagnosed mitochondrial cytopathy and produces severe neuromuscular symptoms. The most frequent cause is a mitochondrial DNA deletion that removes a 4977-base pair segment of DNA that includes several genes encoding for respiratory chain subunits. Treatment of AIDS patients with nucleoside analogs has been reported to cause mtDNA depletion and myopathies. Here, we report that azidothymidine, dideoxyguanosine, and dideoxycytidine cause a depletion of wild-type mtDNA while increasing the levels of deleted mitochondria DNA in Kearns-Sayre syndrome fibroblasts. The result of these effects is a large increase in the relative amounts of delta mtDNA in comparison to wild type mtDNA. We found that Kearns-Sayre syndrome fibroblasts are a mixed population of cells with deleted mtDNA comprising from 0 to over 20% of the total mtDNA in individual cells. Treatment of cloned cell lines with dideoxycytidine did not result in increased levels of delta mtDNA. The results suggest that nucleoside analogs may act to increase the average delta mtDNA levels in a mixed population of cells by preferentially inhibiting the proliferation of cells with little or no delta mtDNA. This raises the possibility that modulation of deleted mtDNA levels may occur by similar mechanisms in vivo, in response to the influence of exogenous agents.

Antiviral Agents↗
PubMed2004

Dideoxynucleoside triphosphate-sensitive DNA polymerase from rice is involved in base excision repair and immunologically similar to mammalian DNA pol beta.

A single polypeptide with ddNTP-sensitive DNA polymerase activity was purified to near homogeneity from the shoot tips of rice seedlings and analysis of the preparations by SDS-PAGE followed by silver staining showed a polypeptide of 67 kDa size. The DNA polymerase activity was found to be inhibitory by ddNTP in both in vitro DNA polymerase activity assay and activity gel analysis. Aphidicolin, an inhibitor of other types of DNA polymerases, had no effect on plant enzyme. The 67 kDa rice DNA polymerase was found to be recognized by the polyclonal antibody (purified IgG) made against rat DNA polymerase beta (pol beta) both in solution and also on Western blot. The recognition was found to be very specific as the activity of Klenow enzyme was unaffected by the antibody. The ability of rice nuclear extract to correct G:U mismatch of oligo-duplex was observed when oligo-duplex with 32P-labeled lower strand containing U (at 22nd position) was used as substrate. Differential appearance of bands at 21-mer, 22-mer, and 51-mer position in presence of dCTP was visible only with G:U mismatch oligo-duplex, but not with G:C oligo-duplex. While ddCTP or polyclonal antibody against rat-DNA pol beta inhibits base excision repair (BER), aphidicolin had no effect. These results for the first time clearly demonstrate the ability of rice nuclear extract to run BER and the involvement of ddNTP-sensitive pol beta type DNA polymerase. Immunological similarity of the ddNTP-sensitive DNA polymerase beta of rice and rat and its involvement in BER revealed the conservation of structure and function of ddNTP-sensitive DNA pol beta in plant and animal.

Aging↗
PubMed1992

Synthesis and anti-HIV activity of 4'-thio-2',3'-dideoxynucleosides.

A series of 2',3'-dideoxy-4'-thionucleoside analogues of purines and pyrimidines, including 4'-thioddI (17), 4'-thioddC (27), and 4'-thioAZT (34), were synthesized and evaluated for their inhibitory activity against human immunodeficiency virus (HIV). A stereospecific synthesis of the 2,3-dideoxy-4-thioribofuranosyl carbohydrate precursor 11 starting with L-glutamic acid is described. 2',3'-Dideoxy-4'-thiocytidine (27) displayed significant, but modest activity in vitro against human immunodeficiency virus.

Antiviral Agents↗
PubMed1992

Potential prodrug derivatives of 2',3'-didehydro-2',3'-dideoxynucleosides. Preparations and antiviral activities.

The preparations and antiviral activities of a series (4-17) of potential prodrug forms of the antivirals 2',3'-didehydro-2',3'-dideoxyadenosine (D4A) and 2',3'-didehydro-2',3'-dideoxycytosine (D4C) are reported. The 5'-phenyl- and 5'-methylphosphonates (4, 6, 8, and 10) and their phosphonothionate congeners (5, 7, 9, and 11), with the exception of 10, were inactive in vitro against HIV-1 and HIV-2. However, the 5'-phenyl, 5'-methyl, and 5'-(3'-thymidyl) phosphate diesters (12-17) demonstrated inhibition of the cytopathic effect of HIV-1 and HIV-2 (EC50 approximately 1-60 microM) and cytotoxicities (CC50 approximately 35-200 microM) at concentration levels comparable to those of their parent compounds, D4A and D4C. This strongly suggests that the diesters are hydrolyzed to the nucleosides D4A and D4C and/or their 5'-monophosphates. The facile hydrolysis of 12 and 13 to these products was demonstrated in a medium containing 10% fetal calf serum. The molecules can serve as ready prodrug sources of the free nucleosides and their 5'-monophosphates. Evidently, the phosphonates and phosphonothionates are not similarly cleaved, nor are they phosphorylated to form antivirally active or cytotoxic products. The importance of intracellular formation of these products in the activation of 12-17 is less clear. Potential prodrugs 4-17 are all stable in aqueous solution for hours with the exception of 14. Conjugates 4-17 showed no activity against a series of DNA and RNA viruses.

Antiviral Agents↗
PubMed1989

1',2'-seco-dideoxynucleosides as potential anti-HIV agents.

1',2'-seco-2',3'-Dideoxycytidine (12), -guanosine (14), -adenosine (16), and -inosine (18) were prepared from (R)-benzylglycidol as potential anti-HIV agents. When compared to ddAdo in protecting ATH8 cells, they were found to be inactive.

Antiviral Agents↗