| ID Source | ID |
|---|---|
| PubMed CID | 150851 |
| CHEMBL ID | 2385615 |
| SCHEMBL ID | 221951 |
| Synonym |
|---|
| 2'-fluoro-2'-deoxyuridine |
| 784-71-4 |
| 2'-deoxy-2'-fluorouridine , |
| uridine, 2'-deoxy-2'-fluoro- |
| 1-(3-fluoro-4-hydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl)-1h-pyrimidine-2,4-dione |
| 1-[(2r,3r,4r,5r)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]pyrimidine-2,4-dione |
| STK368458 |
| 1-[(2r,3r,4r,5r)-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione |
| 1-((2s,3s,4s,5s)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-yl)pyrimidine-2,4(1h,3h)-dione;2'-deoxy-2'-fluorouridine; 2-fdu |
| A839431 |
| 2'fluoro-2'-deoxyuridine |
| unii-y2yc903qw8 |
| y2yc903qw8 , |
| CHEMBL2385615 |
| AKOS015896926 |
| 1-(2-deoxy-2-fluoro-.beta,-d-ribofuranosyl)uracil |
| 1-((2r,3r,4r,5r)-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl)pyrimidine-2,4-dione |
| HG1163 |
| SCHEMBL221951 |
| 1-(2-deoxy-2-fluoro-beta-d-ribofuranosyl)uracil |
| 2'-deoxy-2'-fluoro-uridine |
| 2'-deoxy-2'- fluorouridine |
| UIYWFOZZIZEEKJ-XVFCMESISA-N |
| J-700032 |
| 2'-deoxy-2'-(r)-fluoro-uridine |
| 2'-deoxy-2'-fluoro-l-uridine |
| 1-((2r,3r,4r,5r)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1h,3h)-dione |
| mfcd01317293 |
| CS-W014119 |
| DS-10495 |
| 622785-69-7 |
| Q27294189 |
| 1-(2-deoxy-2-fluoropentofuranosyl)-4-hydroxypyrimidin-2(1h)-one |
| DTXSID50999738 |
| HY-W013403 |
| PD158307 |
| BP-58615 |
2'fluoro-2'-deoxyuridine co-occurs with 64 substances in research.
| Substance | Studies | Trials | Trials (%) | Studies (pre-1990) | Studies (1990-2000) | Studies (2001-2010) | Studies (2011-2020) | Studies (post-2020) |
|---|---|---|---|---|---|---|---|---|
| Floxuridine | 9 | 0 | 0.00 | 3 | 4 | 1 | 1 | 0 |
| Nucleosides | 3 | 0 | 0.00 | 2 | 0 | 0 | 0 | 1 |
| Uracil | 3 | 0 | 0.00 | 2 | 0 | 1 | 0 | 0 |
| Deoxyuridine | 3 | 0 | 0.00 | 2 | 1 | 0 | 0 | 0 |
| Antiviral Agents | 3 | 0 | 0.00 | 1 | 0 | 0 | 2 | 0 |
| RNA | 2 | 0 | 0.00 | 0 | 0 | 0 | 2 | 0 |
| Fluorine | 2 | 0 | 0.00 | 0 | 0 | 1 | 1 | 0 |
| DNA Glycosylases | 2 | 0 | 0.00 | 0 | 1 | 1 | 0 | 0 |
| Uracil-DNA Glycosidase | 2 | 0 | 0.00 | 0 | 1 | 1 | 0 | 0 |
| Ribonucleosides | 2 | 0 | 0.00 | 0 | 1 | 0 | 1 | 0 |
| Ribonuclease H | 2 | 0 | 0.00 | 0 | 2 | 0 | 0 | 0 |
| 2'-chloro-2'-deoxyuridine | 2 | 0 | 0.00 | 2 | 0 | 0 | 0 | 0 |
| DNA | 2 | 0 | 0.00 | 1 | 1 | 0 | 0 | 0 |
| Cytokines | 1 | 0 | 0.00 | 0 | 0 | 0 | 1 | 0 |
| Receptors, Pattern Recognition | 1 | 0 | 0.00 | 0 | 0 | 0 | 1 | 0 |
| TLR3 protein, human | 1 | 0 | 0.00 | 0 | 0 | 0 | 1 | 0 |
| Toll-Like Receptor 3 | 1 | 0 | 0.00 | 0 | 0 | 0 | 1 | 0 |
| nucleoside deoxyribosyltransferase | 1 | 0 | 0.00 | 0 | 0 | 0 | 0 | 1 |
| Escherichia coli Proteins | 1 | 0 | 0.00 | 0 | 0 | 1 | 0 | 0 |
| Nucleic Acid Heteroduplexes | 1 | 0 | 0.00 | 0 | 0 | 1 | 0 | 0 |
| Solutions | 1 | 0 | 0.00 | 0 | 0 | 1 | 0 | 0 |
| Leucine | 1 | 0 | 0.00 | 0 | 0 | 1 | 0 | 0 |
| Leucine | 1 | 0 | 0.00 | 0 | 0 | 1 | 0 | 0 |
| 2'-iodo-2'-deoxyuridine | 1 | 0 | 0.00 | 1 | 0 | 0 | 0 | 0 |
| 2'-bromo-2'-deoxyuridine | 1 | 0 | 0.00 | 1 | 0 | 0 | 0 | 0 |
| Bromodeoxyuridine | 1 | 0 | 0.00 | 1 | 0 | 0 | 0 | 0 |
| Idoxuridine | 1 | 0 | 0.00 | 1 | 0 | 0 | 0 | 0 |
| Thymidine | 1 | 0 | 0.00 | 1 | 0 | 0 | 0 | 0 |
| Hydroxyl Radical | 1 | 0 | 0.00 | 0 | 1 | 0 | 0 | 0 |
| ribonuclease HI | 1 | 0 | 0.00 | 0 | 1 | 0 | 0 | 0 |
| Fluorine Radioisotopes | 1 | 0 | 0.00 | 0 | 1 | 0 | 0 | 0 |
| Prodrugs | 1 | 0 | 0.00 | 0 | 1 | 0 | 0 | 0 |
| Arabinofuranosyluracil | 1 | 0 | 0.00 | 0 | 1 | 0 | 0 | 0 |
| Oligonucleotides | 1 | 0 | 0.00 | 0 | 1 | 0 | 0 | 0 |
| Thymidylate Synthase | 1 | 0 | 0.00 | 0 | 1 | 0 | 0 | 0 |
| clevudine | 1 | 0 | 0.00 | 0 | 1 | 0 | 0 | 0 |
| Enzyme Inhibitors | 1 | 0 | 0.00 | 0 | 1 | 0 | 0 | 0 |
| Furans | 1 | 0 | 0.00 | 0 | 1 | 0 | 0 | 0 |
| N-Glycosyl Hydrolases | 1 | 0 | 0.00 | 0 | 1 | 0 | 0 | 0 |
| furan | 1 | 0 | 0.00 | 0 | 1 | 0 | 0 | 0 |
| Oligonucleotide Probes | 1 | 0 | 0.00 | 0 | 1 | 0 | 0 | 0 |
| RNA, Bacterial | 1 | 0 | 0.00 | 0 | 1 | 0 | 0 | 0 |
| RNA, Ribosomal, 5S | 1 | 0 | 0.00 | 0 | 1 | 0 | 0 | 0 |
| RNA, Transfer, Phe | 1 | 0 | 0.00 | 0 | 1 | 0 | 0 | 0 |
| Deoxycytidine | 1 | 0 | 0.00 | 0 | 1 | 0 | 0 | 0 |
| 2'-fluoro-2'-deoxycytidine | 1 | 0 | 0.00 | 0 | 1 | 0 | 0 | 0 |
| Carbon Radioisotopes | 1 | 0 | 0.00 | 1 | 0 | 0 | 0 | 0 |
| Radioisotopes | 1 | 0 | 0.00 | 1 | 0 | 0 | 0 | 0 |
| Chlorine | 1 | 0 | 0.00 | 1 | 0 | 0 | 0 | 0 |
| Uridine | 1 | 0 | 0.00 | 1 | 0 | 0 | 0 | 0 |
| Bromine Radioisotopes | 1 | 0 | 0.00 | 1 | 0 | 0 | 0 | 0 |
| Iodine Radioisotopes | 1 | 0 | 0.00 | 1 | 0 | 0 | 0 | 0 |
| 5-bromo-1-(2-fluoro-2-deoxyribofuranosyl)uracil | 1 | 0 | 0.00 | 1 | 0 | 0 | 0 | 0 |
| 5-iodo-1-(2-fluoro-2-deoxyribofuranosyl)uracil | 1 | 0 | 0.00 | 1 | 0 | 0 | 0 | 0 |
| Pentosyltransferases | 1 | 0 | 0.00 | 0 | 0 | 0 | 0 | 1 |
| Indicators and Reagents | 1 | 0 | 0.00 | 1 | 0 | 0 | 0 | 0 |
| Cytosine | 1 | 0 | 0.00 | 1 | 0 | 0 | 0 | 0 |
| Organophosphonates | 1 | 0 | 0.00 | 0 | 0 | 0 | 1 | 0 |
| DNA-Directed RNA Polymerases | 1 | 0 | 0.00 | 0 | 0 | 0 | 1 | 0 |
| Aza Compounds | 1 | 0 | 0.00 | 0 | 0 | 0 | 1 | 0 |
| Nucleic Acid Synthesis Inhibitors | 1 | 0 | 0.00 | 0 | 0 | 0 | 1 | 0 |
| RNA, Mitochondrial | 1 | 0 | 0.00 | 0 | 0 | 0 | 1 | 0 |
| RNA-Dependent RNA Polymerase | 1 | 0 | 0.00 | 0 | 0 | 0 | 1 | 0 |
| DNA-Directed DNA Polymerase | 1 | 0 | 0.00 | 0 | 0 | 0 | 1 | 0 |
| Adenosine | 1 | 0 | 0.00 | 0 | 0 | 0 | 1 | 0 |
2'fluoro-2'-deoxyuridine co-occurs with 3 related conditions in research.
| Condition | Studies | Trials | pre-1990 | 1990-2000 | 2001-2010 | 2011-2020 | post-2020 |
|---|---|---|---|---|---|---|---|
| Neoplasms | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| Carcinoma 256, Walker | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Lung Neoplasms | 2 | 0 | 2 | 0 | 0 | 0 | 0 |
2'fluoro-2'-deoxyuridine co-occurs with 102 topic(s) in research.
| Topic | Studies | Trials | pre-1990 | 1990-2000 | 2001-2010 | 2011-2020 | post-2020 |
|---|---|---|---|---|---|---|---|
| Escherichia coli | 3 | 0 | 0 | 2 | 0 | 0 | 0 |
| Kinetics | 3 | 0 | 1 | 1 | 0 | 0 | 0 |
| Nucleosides | 3 | 0 | 2 | 0 | 0 | 0 | 0 |
| Pentosyltransferases | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Substrate Specificity | 2 | 0 | 0 | 0 | 1 | 0 | 0 |
| Cell Death | 1 | 0 | 0 | 0 | 0 | 1 | 0 |
| Cytokines | 1 | 0 | 0 | 0 | 0 | 1 | 0 |
| Floxuridine | 9 | 0 | 3 | 4 | 1 | 1 | 0 |
| Gene Expression Regulation | 1 | 0 | 0 | 0 | 0 | 1 | 0 |
| Nucleic Acid Conformation | 2 | 0 | 0 | 1 | 0 | 1 | 0 |
| RNA | 2 | 0 | 0 | 0 | 0 | 2 | 0 |
| Receptors, Pattern Recognition | 1 | 0 | 0 | 0 | 0 | 1 | 0 |
| Toll-Like Receptor 3 | 1 | 0 | 0 | 0 | 0 | 1 | 0 |
| Amino Acid Substitution | 1 | 0 | 0 | 0 | 1 | 0 | 0 |
| Binding Sites | 1 | 0 | 0 | 0 | 1 | 0 | 0 |
| Catalysis | 1 | 0 | 0 | 0 | 1 | 0 | 0 |
| DNA Glycosylases | 2 | 0 | 0 | 1 | 1 | 0 | 0 |
| Enzyme Stability | 1 | 0 | 0 | 0 | 1 | 0 | 0 |
| Escherichia coli Proteins | 1 | 0 | 0 | 0 | 1 | 0 | 0 |
| Fluorine | 2 | 0 | 0 | 0 | 1 | 1 | 0 |
| Hydrogen Bonding | 2 | 0 | 0 | 1 | 1 | 0 | 0 |
| Leucine | 1 | 0 | 0 | 0 | 1 | 0 | 0 |
| Models, Molecular | 2 | 0 | 0 | 1 | 1 | 0 | 0 |
| Nuclear Magnetic Resonance, Biomolecular | 1 | 0 | 0 | 0 | 1 | 0 | 0 |
| Nucleic Acid Heteroduplexes | 1 | 0 | 0 | 0 | 1 | 0 | 0 |
| Solutions | 1 | 0 | 0 | 0 | 1 | 0 | 0 |
| Spectrometry, Fluorescence | 1 | 0 | 0 | 0 | 1 | 0 | 0 |
| Thermodynamics | 1 | 0 | 0 | 0 | 1 | 0 | 0 |
| Uracil | 3 | 0 | 2 | 0 | 1 | 0 | 0 |
| Uracil-DNA Glycosidase | 2 | 0 | 0 | 1 | 1 | 0 | 0 |
| Binding, Competitive | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Biological Transport, Active | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Bromodeoxyuridine | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Deoxyuridine | 3 | 0 | 2 | 1 | 0 | 0 | 0 |
| Erythrocyte Membrane | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Erythrocytes | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Idoxuridine | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Structure-Activity Relationship | 4 | 0 | 3 | 0 | 0 | 1 | 0 |
| Thymidine | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Base Sequence | 3 | 0 | 0 | 3 | 0 | 0 | 0 |
| Hydroxyl Radical | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| Molecular Sequence Data | 3 | 0 | 0 | 3 | 0 | 0 | 0 |
| Oligonucleotides | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| Protein Structure, Tertiary | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| Ribonuclease H | 2 | 0 | 0 | 2 | 0 | 0 | 0 |
| Ribonucleosides | 2 | 0 | 0 | 1 | 0 | 1 | 0 |
| Arabinofuranosyluracil | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| Cell Division | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| DNA | 2 | 0 | 1 | 1 | 0 | 0 | 0 |
| Fluorine Radioisotopes | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| Methylation | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| Phosphorylation | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| Prodrugs | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| Thymidylate Synthase | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| Tumor Cells, Cultured | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| Electrophoresis, Polyacrylamide Gel | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| Enzyme Inhibitors | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| Furans | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| Herpesvirus 1, Human | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| Isomerism | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| Models, Chemical | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| Molecular Mimicry | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| N-Glycosyl Hydrolases | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| Deoxycytidine | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| Oligonucleotide Probes | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| RNA, Bacterial | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| RNA, Ribosomal, 5S | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| RNA, Transfer, Phe | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| Carbon Radioisotopes | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Chlorine | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Radioisotopes | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Rats | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Rats, Inbred Strains | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Tissue Distribution | 2 | 0 | 2 | 0 | 0 | 0 | 0 |
| Uridine | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Biological Transport | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Bromine Radioisotopes | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Chemical Phenomena | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Chemistry | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Iodine Radioisotopes | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Isotope Labeling | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Molecular Structure | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Antiviral Agents | 3 | 0 | 1 | 0 | 0 | 2 | 0 |
| Cell Line | 2 | 0 | 1 | 0 | 0 | 1 | 0 |
| Chlorocebus aethiops | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Cytosine | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Indicators and Reagents | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Kidney | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Simplexvirus | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Viral Plaque Assay | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| DNA-Directed RNA Polymerases | 1 | 0 | 0 | 0 | 0 | 1 | 0 |
| Drug Evaluation, Preclinical | 2 | 0 | 0 | 0 | 0 | 2 | 0 |
| Hepacivirus | 1 | 0 | 0 | 0 | 0 | 1 | 0 |
| Organophosphonates | 1 | 0 | 0 | 0 | 0 | 1 | 0 |
| Virus Replication | 2 | 0 | 0 | 0 | 0 | 2 | 0 |
| Adenosine | 1 | 0 | 0 | 0 | 0 | 1 | 0 |
| Aza Compounds | 1 | 0 | 0 | 0 | 0 | 1 | 0 |
| DNA-Directed DNA Polymerase | 1 | 0 | 0 | 0 | 0 | 1 | 0 |
| Nucleic Acid Synthesis Inhibitors | 1 | 0 | 0 | 0 | 0 | 1 | 0 |
| RNA, Mitochondrial | 1 | 0 | 0 | 0 | 0 | 1 | 0 |
| RNA-Dependent RNA Polymerase | 1 | 0 | 0 | 0 | 0 | 1 | 0 |
| Respiratory Syncytial Viruses | 1 | 0 | 0 | 0 | 0 | 1 | 0 |
13 studies published for this drug since 1983
| Studies | Pre-1990 | 1990-2000 | 2001-2010 | 2011-2020 | Post-2020 |
|---|---|---|---|---|---|
| 13 | 4 | 4 | 1 | 3 | 1 |
There are 13 studies published for this drug
| Publication Type | Studies (#) | Studies (%) |
|---|---|---|
| Journal Article | 13 | 100.00 |
| Research Support, Non-U.S. Gov't | 5 | 38.46 |
| Research Support, U.S. Gov't, P.H.S. | 2 | 15.38 |
| Comparative Study | 2 | 15.38 |
| Research Support, N.I.H., Extramural | 1 | 7.69 |
| Evaluation Study | 1 | 7.69 |
0 trials are available for 2'fluoro-2'-deoxyuridine (max 10)
| Article |
|---|
0 reviews are available for 2'fluoro-2'-deoxyuridine (max 10)
| Article |
|---|
0 case studies are available for 2'fluoro-2'-deoxyuridine (max 10)
| Article |
|---|
13 other studies are available for 2'fluoro-2'-deoxyuridine (max 10)
| Article |
|---|
Isolation and Characterization of Engineered Nucleoside Deoxyribosyltransferase with Enhanced Activity Toward 2'-Fluoro-2'-Deoxynucleoside.
Nucleoside deoxyribosyltransferase (NDT) is an enzyme that replaces the purine or pyrimidine base of 2'-deoxyribonucleoside. This enzyme is generally used in the nucleotide salvage pathway in vivo and synthesizes many nucleoside analogs in vitro for various biotechnological purposes. Since NDT is known to exhibit relatively low reactivity toward nucleoside analogs such as 2'-fluoro-2'-deoxynucleoside, it is necessary to develop an enhanced NDT mutant enzyme suitable for nucleoside analogs. In this study, molecular evolution strategy via error-prone PCR was performed with ndt gene derived from |
2'Fluoro Modification Differentially Modulates the Ability of RNAs to Activate Pattern Recognition Receptors.
Although the use of RNAs has enormous therapeutic potential, these RNA-based therapies can trigger unwanted inflammatory responses by the activation of pattern recognition receptors (PRRs) and cause harmful side effects. In contrast, the immune activation by therapeutic RNAs can be advantageous for treating cancers. Thus, the immunogenicity of therapeutic RNAs should be deliberately controlled depending on the therapeutic applications of RNAs. In this study, we demonstrated that RNAs containing 2'fluoro (2'F) pyrimidines differentially controlled the activation of PRRs. The activity of RNAs that stimulate toll-like receptors 3 and 7 was abrogated by the incorporation of 2'F pyrimidine. By contrast, incorporation of 2'F pyrimidines enhanced the activity of retinoic acid-inducible gene 1-stimulating RNAs. Furthermore, we found that transfection with RNAs containing 2'F pyrimidine and 5' triphosphate (5'ppp) increased cell death and interferon-β expression in human cancer cells compared with transfection with 2'hydroxyl 5'ppp RNAs, whereas RNAs containing 2'O-methyl pyrimidine and 5'ppp completely abolished the induction of cell death and cytokine expression in the cells. Our findings suggest that incorporation of 2'F and 2'O-methyl nucleosides is a facile approach to differentially control the ability of therapeutic RNAs to activate or limit immune and inflammatory responses depending on therapeutic applications. |
Discovery of β-D-2'-deoxy-2'-α-fluoro-4'-α-cyano-5-aza-7,9-dideaza adenosine as a potent nucleoside inhibitor of respiratory syncytial virus with excellent selectivity over mitochondrial RNA and DNA polymerases.
Novel 4'-substituted β-d-2'-deoxy-2'-α-fluoro (2'd2'F) nucleoside inhibitors of respiratory syncytial virus (RSV) are reported. The introduction of 4'-substitution onto 2'd2'F nucleoside analogs resulted in compounds demonstrating potent cell based RSV inhibition, improved inhibition of the RSV polymerase by the nucleoside triphosphate metabolites, and enhanced selectivity over incorporation by mitochondrial RNA and DNA polymerases. Selectivity over the mitochondrial polymerases was found to be extremely sensitive to the specific 4'-substitution and not readily predictable. Combining the most potent and selective 4'-groups from N-nucleoside analogs onto a 2'd2'F C-nucleoside analog resulted in the identification of β-D-2'-deoxy-2'-α-fluoro-4'-α-cyano-5-aza-7,9-dideaza adenosine as a promising nucleoside lead for RSV. |
Evaluation of 2'-α-fluorine modified nucleoside phosphonates as potential inhibitors of HCV polymerase.
Ribonucleoside phosphonate analogues containing 2'-α-fluoro modifications were synthesized and their potency evaluated against HCV RNA polymerase. The diphosphophosphonate (triphosphate equivalent) adenine and cytidine analogues displayed potent inhibition of the HCV polymerase in the range of 1.9-2.1 μM, but only modest cell-based activity in the HCV replicon. Pro-drugs of the parent nucleoside phosphonates improved the cell-based activity. |
Recognition of an unnatural difluorophenyl nucleotide by uracil DNA glycosylase.
The DNA repair enzyme uracil DNA glycosylase (UDG) utilizes base flipping to recognize and remove unwanted uracil bases from the genome but does not react with its structural congener, thymine, which differs by a single methyl group. Two factors that determine whether an enzyme flips a base from the duplex are its shape and hydrogen bonding properties. To probe the role of these factors in uracil recognition by UDG, we have synthesized a DNA duplex that contains a single difluorophenyl (F) nucleotide analogue that is an excellent isostere of uracil but possesses no hydrogen bond donor or acceptor groups. By using binding affinity measurements, solution (19)F NMR, and solid state (31)P[(19)F] rotational-echo double-resonance (REDOR) NMR measurements, we establish that UDG partially unstacks F from the duplex. However, due to the lack of hydrogen bonding groups that are required to support an open-to-closed conformational transition in UDG, F cannot stably dock in the UDG active site. We propose that F attains a metastable unstacked state that mimics a previously detected intermediate on the uracil-flipping pathway and suggest structural models of the metastable state that are consistent with the REDOR NMR measurements. |
Selective inhibition of herpes simplex virus type-1 uracil-DNA glycosylase by designed substrate analogs.
Cytosine deamination and the misincorporation of 2'-dUrd into DNA during replication result in the presence of uracil in DNA. Uracil-DNA glycosylases (UDGs) initiate the excision repair of this aberrant base by catalyzing the hydrolysis of the N-glycosidic bond. UDGs are expressed by nearly all known organisms, including some viruses, in which the functional role of the UDG protein remains unresolved. This issue could in principle be addressed by the availability of designed synthetic inhibitors that target the viral UDG without affecting the endogenous human UDG. Here, we report that double-stranded and single-stranded oligonucleotides incorporating either of two dUrd analogs tightly bind and inhibit the activity of herpes simplex virus type-1 (HSV-1) UDG. Both inhibitors are exquisitely specific for the HSV-1 UDG over the human UDG. These inhibitors should prove useful in structural studies aimed at understanding substrate recognition and catalysis by UDGs, as well as in elucidating the biologic role of UDGs in the life cycle of herpesviruses. |
Suicide prodrugs activated by thymidylate synthase: rationale for treatment and noninvasive imaging of tumors with deoxyuridine analogues.
Most tumors are resistant to therapy by thymidylate synthase (TS) inhibitors due to their high levels of TS. Instead of inhibiting TS, we hypothesized that it was possible to use this enzyme to activate suicide prodrugs (deoxyuridine analogues) to more toxic species (thymidine analogues). Tumors with high levels of TS could be particularly sensitive to deoxyuridine analogues because they would be more efficient in producing the toxic methylated species. Furthermore, the accumulation of methylated species within tumors could be visualized externally if a tracer dose of the deoxyuridine analogue was tagged with an isotope, preferably a positron emitter, such as 18F. Higher accumulation of isotope indicates higher activity of TS and lower sensitivity of the tumor to TS inhibitors, but perhaps more sensitivity to therapy with deoxyuridine analogues as suicide prodrugs. 2'-F-ara-deoxyuridine (FAU) was used as a prototype to demonstrate these concepts experimentally. FAU readily entered cells and was phosphorylated, methylated, and subsequently incorporated into cellular DNA. Among different cell lines, FAU produced varying degrees of growth inhibition. Greater DNA incorporation (e.g., for CEM and U-937 cells) was reflected as increased toxicity. FAU produced less DNA incorporation in Raji or L1210 cells, and growth rate was minimally decreased. As the first demonstration that cells with high levels of TS activity can be more vulnerable to therapy than cells with low TS activity, this preliminary work suggests a new therapeutic approach for common human tumors that were previously resistant. Furthermore, it appears that the TS activity of tumors could be noninvasively imaged in situ by tracer doses of [18F]FAU and that this phenotypic information could guide patient therapy. |
Recognition of 2'-hydroxyl groups by Escherichia coli ribonuclease HI.
In order to investigate the hydrogen-bonding interactions between Escherichia coli ribonuclease HI and the 2'-hydroxyl functions of the substrate, oligonucleotide duplexes containing 2'-amino-2'-deoxyuridine or 2'-fluoro-2'-deoxyuridine at a specific site were used, and their affinities for the enzyme were determined by kinetic analyses. The results indicate that the hydroxyl groups of the nucleoside 3'-adjacent to the cleaved phosphodiester linkage and the second nucleoside 5' to the cleaved phosphodiester act as both a proton donor and an acceptor and as a proton acceptor, respectively, in the enzyme-substrate complex. A molecular model was constructed using the interactions derived from the results. |
Nucleosides. 123. Synthesis of antiviral nucleosides: 5-substituted 1-(2-deoxy-2-halogeno-beta-D-arabinofuranosyl)cytosines and -uracils. Some structure-activity relationships.
The syntheses of several 2'-halogeno-5-substituted-arabinofuranosylcytosines and -uracils are described, and relationships of structure to anti herpes virus activity in vitro were examined. Those arabinonucleosides containing the 2'-fluoro function exhibit, generally, more potent anti herpes virus (HSV) activity than do their 2'-chloro of 2'-bromo analogues. The importance of the fluorine in the 2'-"up" (arabino) configuration for enhancement of antiviral effectiveness is demonstrated by the superior activity of 2'-fluoro-5-iodo-ara-C [3a, FIAC] to that of 2'-fluoro-5-iodo-ribo-C. Of all the nucleosides tested herein, FIAC exhibited the most potent in vitro activity against HSV. 2'-Chloro-5-iodo- and -5-methyl-ara-C (3b and 4b) were 37 to greater than 500 times more effective in vitro against HSV type 2 than against type 1, suggesting that these latter derivatives might serve clinically as useful probes to distinguish between HSV types 1 and 2 in the diagnosis of HSV infections in man. |
Interaction of 2'-halogeno-2'-deoxyuridines with the human erythrocyte nucleoside transport mechanism.
The efflux of radioactive thymidine from human erythrocytes at 25 degrees was accelerated in the presence of extracellular 2'-fluoro-2'-deoxyuridine to a maximal velocity 120% of that observed in the presence of extracellular nonradioactive thymidine. Efflux in the presence of 2'-chloro-2'-deoxyuridine and 2'-bromo-2'-deoxyuridine did not exceed 56% and 49%, respectively. 2'-Iodo-2'-deoxyuridine did not accelerate thymidine efflux. In comparison, 2'-fluoro-2'-deoxycytidine and 2'-deoxyuridine accelerated thymidine efflux to maximal velocities of 170% and 91%, respectively. The half-saturation constant for acceleration of thymidine efflux by 2'-fluoro-2'-deoxycytidine was higher (0.90 mM) than those estimated for the other substances (0.22 mM or lower). Influx competition experiments at 25 degrees showed that all of the above nucleosides competitively inhibited influx of thymidine into human erythrocytes. The Km for the zero-trans influx of thymidine was 0.051 +/- 0.008 mM, while the Ki values for 2'-deoxyuridine and the 2'-halogeno-2'-deoxyuridines were similar, ranging from 0.04 to 0.09 mM. The Ki for 2'-fluoro-2'-deoxycytidine was 0.18 mM. These results suggest that, although all nucleosides tested appeared to bind to the same transport site on the external membrane surface, their ease of transport through the membrane was determined by the properties of the halogen substituent at position 2'. |
9 bioassays available for 2'fluoro-2'-deoxyuridine involving 4 publications, with an average publication age of 22.8 years
| Bioassay | Year | Journal | Article |
|---|---|---|---|
| Inhibition of growth of normal human lymphocytic cells | Journal of medicinal chemistry, 1983 | Feb, Volume: 26, Issue:2 ISSN: 0022-2623 | Nucleosides. 123. Synthesis of antiviral nucleosides: 5-substituted 1-(2-deoxy-2-halogeno-beta-D-arabinofuranosyl)cytosines and -uracils. Some structure-activity relationships. |
| Inhibition constant for influx competition with [6-3H]thymidine in mouse erythrocytes | Journal of medicinal chemistry, 1989 | Jun, Volume: 32, Issue:6 ISSN: 0022-2623 | Synthesis and tumor uptake of 5-82Br- and 5-131I-labeled 5-halo-1-(2-fluoro-2-deoxy-beta-D-ribofuranosyl)uracils. |
| Antiviral activity against RSV A2 infected in human Hep2 cells assessed as protection against virus-induced cytopathic effect after 4 days by Cell-Titer Glo assay | Bioorganic & medicinal chemistry letters, 2015 | Jun-15, Volume: 25, Issue:12 ISSN: 1464-3405 | Discovery of β-D-2'-deoxy-2'-α-fluoro-4'-α-cyano-5-aza-7,9-dideaza adenosine as a potent nucleoside inhibitor of respiratory syncytial virus with excellent selectivity over mitochondrial RNA and DNA polymerases. |
| Inhibition of human mitochondrial DNA polymerase gamma large subunit/DNA polymerase gamma accessory subunit using 32P-D19/D36 as DNA primer/template assessed as single nucleotide incorporation rate at 100 uM after 5 to 90 mins by PAGE analysis relative to | Bioorganic & medicinal chemistry letters, 2015 | Jun-15, Volume: 25, Issue:12 ISSN: 1464-3405 | Discovery of β-D-2'-deoxy-2'-α-fluoro-4'-α-cyano-5-aza-7,9-dideaza adenosine as a potent nucleoside inhibitor of respiratory syncytial virus with excellent selectivity over mitochondrial RNA and DNA polymerases. |
| Inhibition of human mitochondrial RNA polymerase using 5'-32P-R12/D18 as RNA/DNA template assessed as single nucleotide incorporation rate at 500 uM after 0.17 to 30 mins by PAGE analysis | Bioorganic & medicinal chemistry letters, 2015 | Jun-15, Volume: 25, Issue:12 ISSN: 1464-3405 | Discovery of β-D-2'-deoxy-2'-α-fluoro-4'-α-cyano-5-aza-7,9-dideaza adenosine as a potent nucleoside inhibitor of respiratory syncytial virus with excellent selectivity over mitochondrial RNA and DNA polymerases. |
| Inhibition of RSV A2 RNA-dependent RNA polymerase expressed in human Hep2 cells using ATP, GTP, UTP, CTP and 1.5 uCi [alpha-32P] NTP as substrate assessed as reduction of total radiolabled transcript after 90 mins by agarose gel electrophoresis | Bioorganic & medicinal chemistry letters, 2015 | Jun-15, Volume: 25, Issue:12 ISSN: 1464-3405 | Discovery of β-D-2'-deoxy-2'-α-fluoro-4'-α-cyano-5-aza-7,9-dideaza adenosine as a potent nucleoside inhibitor of respiratory syncytial virus with excellent selectivity over mitochondrial RNA and DNA polymerases. |
| Inhibition of HCV 1b NS5b polymerase | Bioorganic & medicinal chemistry letters, 2013 | Jun-01, Volume: 23, Issue:11 ISSN: 1464-3405 | Evaluation of 2'-α-fluorine modified nucleoside phosphonates as potential inhibitors of HCV polymerase. |
| Antiherpetic activity against HSV-1 | Journal of medicinal chemistry, 1983 | Feb, Volume: 26, Issue:2 ISSN: 0022-2623 | Nucleosides. 123. Synthesis of antiviral nucleosides: 5-substituted 1-(2-deoxy-2-halogeno-beta-D-arabinofuranosyl)cytosines and -uracils. Some structure-activity relationships. |
| Antiherpetic activity against HSV-2 | Journal of medicinal chemistry, 1983 | Feb, Volume: 26, Issue:2 ISSN: 0022-2623 | Nucleosides. 123. Synthesis of antiviral nucleosides: 5-substituted 1-(2-deoxy-2-halogeno-beta-D-arabinofuranosyl)cytosines and -uracils. Some structure-activity relationships. |