Synthetic nucleosides and nucleotides. XXXV. Synthesis and biological evaluations of 5-fluoropyrimidine nucleosides and nucleotides of 3-deoxy-beta-D-ribofuranose and related compounds
| Autor: | Toyofumi Yamaguchi, Shunji Izuta, Akiko Yahata, Shigeru Kimura, Mineo Saneyoshi, Mizue Kohsaka-Ichikawa |
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| Rok vydání: | 1995 |
| Předmět: |
DNA polymerase
Stereochemistry Deamination DNA-Directed DNA Polymerase Antiviral Agents chemistry.chemical_compound Mice Trimethylsilyl trifluoromethanesulfonate Salmon Drug Discovery Trifluoroacetic acid Animals Nucleotide Leukemia L5178 Phosphorylation chemistry.chemical_classification Cordycepin biology Deoxyadenosines Nucleotides Nucleosides General Chemistry General Medicine Deoxyuridine Pyrimidines chemistry biology.protein Deoxycytidine Rhabdoviridae Cell Division Mutagens |
| Zdroj: | Chemicalpharmaceutical bulletin. 43(11) |
| ISSN: | 0009-2363 |
| Popis: | 1-O-Acetyl-2,5-di-O-p-chlorobenzoyl-3-deoxy-D-ribofuranose (1), derived from the antibiotic cordycepin was coupled with trimethylsilylated derivatives (2a-c) of N4-propionylcytosine, N4-p-toluoyl-5-fluorocytosine and 5-fluorouracil in the presence of trimethylsilyl trifluoromethanesulfonate (TMS-triflate) to give fully acylated nucleosides (3a-b and 3d, respectively). Selective removal of the N4-propionyl group of 3a by treatment with hydrazine hydrate gave 2',5'-di-O-p-chlorobenzoyl-3'-deoxycytidine (4). Deamination of 4 with sodium nitrite in trifluoroacetic acid afforded 2',5'-di-O-p-chlorobenzoyluridine (3c) in good yield. Compounds 3a-d were saponified to give free 3'-deoxycytidine (5a), 5-fluoro-3'-deoxycytidine (5b), 3'-deoxyuridine (5c), and 5-fluoro-3'-deoxyuridine (5d), respectively. These 3'-deoxyribonucleosides (5a-d) were then converted to corresponding 5'-monophosphate and further phosphorylated to the 5'-triphosphates by the phosphoroimidazolidate method. The nucleosides (5a-d) were examined for growth-inhibitory effects on mouse leukemic L5178Y cells, and their IC50 values (microgram/ml) were 1.8, 33, 6.5, and 18, respectively. On the other hand, the antiviral activities of these compounds on a rhabdovirus, infectious hematopoietic necrosis virus (IHNV), were moderate (IC50 = 100-500 micrograms/ml in CHSE-214 cells). The 5'-triphosphates showed remarkable inhibitory effects on DNA polymerase beta and DNA polymerase alpha-primase purified from testes of the cherry salmon, Oncorhynchus masou, but not on common DNA polymerase alpha from same source. |
| Databáze: | OpenAIRE |
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