Synthetic nucleosides and nucleotides. XXXV. Synthesis and biological evaluations of 5-fluoropyrimidine nucleosides and nucleotides of 3-deoxy-beta-D-ribofuranose and related compounds.
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.
Saneyoshi
M
M
Department of Biological Sciences, Nishi-Tokyo University, Yamanashi, Japan.
Kohsaka-Ichikawa
M
M
Yahata
A
A
Kimura
S
S
Izuta
S
S
Yamaguchi
T
T
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004259:DNA-Directed DNA Polymerase / Q000187:drug effects; D003839:Deoxyadenosines / Q000737:chemistry / Q000378:metabolism; D007940:Leukemia L5178; D051379:Mice; D009153:Mutagens / Q000737:chemistry / Q000378:metabolism; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D009711:Nucleotides / Q000138:chemical synthesis* / Q000494:pharmacology; D010766:Phosphorylation; D011743:Pyrimidines / Q000378:metabolism*; D012209:Rhabdoviridae / Q000187:drug effects; D012474:Salmon
D000998:Antiviral Agents; D003839:Deoxyadenosines; D009153:Mutagens; D009705:Nucleosides; D009711:Nucleotides; D011743:Pyrimidines; C029269:5-fluoropyrimidine; D004259:DNA-Directed DNA Polymerase; C058120:cordycepin