Nucleosides. 110. Synthesis and antiherpes virus activity of some 2'-fluoro-2'-deoxyarabinofuranosylpyrimidine nucleosides

Watanabe, Kyoichi A.; Reichman, Uri; Hirota, Kosaku; López, Carlos; Fox, Jack J.

doi:10.1021/jm00187a005

Cited by 275 publications

(137 citation statements)

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“…One of the best validated reporter genes is the Herpes Simplex Virus Type 1 thymidine kinase (HSV1-tk), which can phosphorylate various substrates. A series of 5-substituted fluoroarabinofuranosyl nucleosides with high antiviral activity was first developed by Fox et al in the late 1970s [3][4][5][6][7]. From these early studies, radiolabeled markers for HSV1-tk reporter gene expression and cell proliferation, such as 2′-deoxy-2′-fluoro-β-D-arabinofuranosyl-5-iodouracil ([ 14 [10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Semiautomated Radiosynthesis and Biological Evaluation of [18F]FEAU: A Novel PET Imaging Agent for HSV1-tk/sr39tk Reporter Gene Expression

et al. 2007

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2′-Deoxy-2′-[ 18 F]fluoro-5-ethyl-1-β-D-arabinofuranosyluracil ([ 18 F]FEAU) is a promisingradiolabeled nucleoside designed to monitor Herpes Simplex Virus Type 1 thymidine kinase (HSV1-tk) reporter gene expression with positron emission tomography (PET). However, the challenging radiosynthesis creates problems for being able to provide [ 18 F]FEAU routinely. We have developed a routine method using a commercial GE TRACERlab FX-FN radiosynthesis module with customized equipment to provide [ 18 F]FEAU. All radiochemical yields are decay corrected to end-of-bombardment and reported as means±SD. Radiofluorination (33±8%; n=4), bromination (85±8%; n=4), coupling reaction (83±6%; n=4), base hydrolysis steps, and subsequent high-performance liquid chromatography purification afforded purified [ 18 F]FEAU β-anomer in 5±1% overall yield (n=3 runs) after ∼5.5 h and a β/α-anomer ratio of 7.4. Radiochemical/chemical purities and specific activity exceeded 99% and 1.

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Section: Introductionmentioning

confidence: 99%

Semiautomated Radiosynthesis and Biological Evaluation of [18F]FEAU: A Novel PET Imaging Agent for HSV1-tk/sr39tk Reporter Gene Expression

et al. 2007

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“…The selective action of acycloguanosine (ACG), 2'-fluoro-5-iodoaracytosine (FIAC), and (E)-5-(2-bromovinyl)-2'-deoxyuridine (BrVDU) on viral and cellular DNA synthesis in herpes simplex virus type 1 (HSV-1)-infected and uninfected Vero cells has been determined by isopycnic banding of DNA in CsCl gradients. These nucleosides have previously shown a high antiherpes activity (1,5,10,12,13) and are also known to require the presence of herpesvirus-induced thymidine kinase for their antiviral activity (2,5,10).…”

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confidence: 99%

Selective Inhibition of Herpesvirus Deoxyribonucleic Acid Synthesis by Acycloguanosine, 2′-Fluoro-5-Iodo-Aracytosine, and ( E )-5-(2-Bromovinyl)-2′-Deoxyuridine

Larsson

Öberg

1981

Antimicrob Agents Chemother

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The selectivity of inhibition of herpesvirus deoxyribonucleic acid synthesis by acycloguanosine, 2'-fluoro-5-iodo-aracytosine, and (E)-5-(2-bromovinyl)-2'-deoxyuridine was determined by isopycnic banding of 32P-labeled deoxyribonucleic acid from herpesvirus-infected and uninfected cells.An important property of an antiviral compound is the selectivity of its action. Most compounds with a high activity against herpesviruses are nucleoside analogs (3,8,9,11 press). To measure both viral and cellular DNA synthesis, nonconfluent cell cultures and a low multiplicity of infection were used. The selective action of acycloguanosine (ACG), 2'-fluoro-5-iodoaracytosine (FIAC), and (E)-5-(2-bromovinyl)-2'-deoxyuridine (BrVDU) on viral and cellular DNA synthesis in herpes simplex virus type 1 (HSV-1)-infected and uninfected Vero cells has been determined by isopycnic banding of DNA in CsCl gradients. These nucleosides have previously shown a high antiherpes activity (1,5,10,12,13) and are also known to require the presence of herpesvirus-induced thymidine kinase for their antiviral activity (2, 5, 10).ACG showed a high selectivity in the inhibition of viral DNA synthesis ( Fig. 1A to C; Table 1). When viral DNA synthesis was inhibited by 90% at 0.3 uM, only 15% inhibition of cellular DNA synthesis was observed. No effect on DNA synthesis in uninfected cells could be detected at this concentration and 310 ,M ACG was required for a 50% inhibition. The high selectivity found for ACG correlates well with earlier results showing that ACG is phosphorylated to a much higher extent to its mono-, di-, and triphosphate in HSV-1-infected celis than in uninfected cells and that ACG triphosphate is selectively accepted by HSV-1 DNA polymerase, leading to chain termination (5, 7).FIAC was less selective than ACG in the inhibition of viral DNA synthesis in infected cells ( Fig. 1D to F; Table 1). At 0.10 ,uM a 90% inhibition of viral DNA synthesis was obtained, whereas cellular DNA synthesis in infected cells was inhibited by 40%. However, DNA synthesis in uninfected cells was not inhibited at this concentration, and 64 ,LM FIAC was required to obtain a 50% inhibition, which confirms the results of Lopez et al. (10) showing a high selectivity by FIAC when effects on HSV-1 multiplication and cytotoxicity for uninfected Vero cells were compared.BrVDU inhibited viral DNA synthesis by 90% at a concentration of 0.6 uM ( Fig. 1G to I; Table 1). As in the case of FIAC, but not of ACG, the cellular DNA synthesis in infected cells was also affected, to 60%, at this concentration. In the uninfected cells, DNA synthesis was not affected by 0.6 juM BrVDU, and at 440 ,M a 50% inhibition was observed. These results agree with those of De Clercq et al. (1), who have shown previously that BrVDU inhibits HSV-1 multiplication at low concentrations, while not affecting the growth of uninfected cells.In a cell-free assay, BrVDU seems to be selectively phosphorylated by HSV-1 thymidine kinase (A. Larsson, unpublished data

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“…In this study we evaluated the effect of m-dsRNA, a potent interferon inducer, on DHBV replication in duck primary hepatocytes infected with DHBV. We also examined the efficacy of m-dsRNA as compared to that of 1-(2'-deoxy-2'-fluoro-~-D-arabinofuranosyl)-5-methyl uracil (D-FMAU) (Watanabe et al, 1979), a strong inhibitor of hepadnavirus replication, in the same assay system.…”

Section: Discussionmentioning

confidence: 99%

Comparison of Antiviral Effects of Mismatched Double-Stranded RNA and 1 -(2′-Deoxy-2′,-Fluoro-β-D-Arabinofuranosyl)-5-Methyluracil (D-FMAU) against Duck Hepatitis B virus in Vitro

Ijichi

Mitamura

et al. 1997

Antivir Chem Chemother

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SummaryThe effects of mismatched double-stranded RNA [mdsRNA) and 1-12'-deoxy-2'-f1uoro-~-o-arabinofura nosyl)-5-methyl-uracil lo-FMAU) on the replication of duck hepatitis B virus IDHBV) were examined in duck primary hepatocytes infected with DHBV. The 50% inhibitory doses of m-dsRNA and o-FMAU for the replication of DHBV DNA were 0.34±0.06 and 0.007±0.001 Ilg mL-l, respectively. Mismatched dsRNA slightly inhibited the intermediate DHBV DNA at a concentration as high as 1.0 Ilg ml,", whereas the DHBV replicative form was markedly suppressed in the presence of 0.1 Ilg mL-l of o-FMAU. On the other hand, m-dsRNA inhibited DHBV DNA replication even after the compound was removed from the culture medium, while the efficacy of o-FMAU did not persist after the cessation of treatment. The analysis of DHBV RNA revealed that m-dsRNA markedly inhibited DHBV RNA transcription, while. o-FMAU only marginally suppressed the transcription of viral RNA. These results indicate that m-dsRNA inhibits DHBV RNA transcription rather than DHBV DNA replication and that this suppression of DHBV RNA transcription may produce persistent inhibition of DHBV replication.

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Nucleosides. 110. Synthesis and antiherpes virus activity of some 2'-fluoro-2'-deoxyarabinofuranosylpyrimidine nucleosides

Cited by 275 publications

References 4 publications

Semiautomated Radiosynthesis and Biological Evaluation of [18F]FEAU: A Novel PET Imaging Agent for HSV1-tk/sr39tk Reporter Gene Expression

Semiautomated Radiosynthesis and Biological Evaluation of [18F]FEAU: A Novel PET Imaging Agent for HSV1-tk/sr39tk Reporter Gene Expression

Selective Inhibition of Herpesvirus Deoxyribonucleic Acid Synthesis by Acycloguanosine, 2′-Fluoro-5-Iodo-Aracytosine, and ( E )-5-(2-Bromovinyl)-2′-Deoxyuridine

Comparison of Antiviral Effects of Mismatched Double-Stranded RNA and 1 -(2′-Deoxy-2′,-Fluoro-β-D-Arabinofuranosyl)-5-Methyluracil (D-FMAU) against Duck Hepatitis B virus in Vitro

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