Synthetic Nucleosides and Nucleotides. XXXV. Synthesis and Biological Evaluations of 5-Fluoropyrimidine Nucleosides and Nucleotides of 3-Deoxy-β-D-ribofuranose and Related Compounds

Abstract

l-O-Acetyl-2,5-di-O-β-chlorobenzoyl-3-deoxy-D-ribofuranose (1), derived from the antibiotic cordycepin was coupled with trimethylsilylated derivatives (2a—c) of N-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-ρ-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 (μg/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 μg/ml in CHSE-214 cells). The 5’-triphosphates showed remarkable inhibitory effects on DNA polymerase β and DNA polymerase a-primase purified from testes of the cherry salmon, Oncorhynchus masou, but not on common DNA polymerase a from same source. © 1995, The Pharmaceutical Society of Japan. All rights reserved.