Nucleic acid related compounds. 40. Synthesis and biological activities of 5-alkynyluracil nucleosides.
Coupling of terminal alkynes with 5-iodo-1-(2,3,5-tri-O-p-toluyl-beta-D-arabinofuranosyl)uracil and 5-iodo-3',5'-di-O-p-toluyl-2'-deoxyuridine proceeded readily in triethylamine with catalytic quantities of bis(triphenylphosphine)-palladium(II) chloride and copper(I) iodide. The resulting products were deprotected to give 5-alkynyl-1-beta-D-arabinofuranosyluracil and 5-alkynyl-2'-deoxyuridine nucleosides. The 5-ethynyl, followed by 5-propynyl, products had the highest antiviral potency, with the 2'-deoxy derivatives being more effective than the arabinosyl compounds. Activity was weak at hexynyl and disappeared at heptynyl. Inclusion of an omega-hydroxy function diminished the antiviral effect. None of the 5-alkynyluracil nucleosides tested had sufficient selectivity to qualify as a candidate antiviral drug. Several of the compounds exerted an inhibitory action on thymidylate synthetase, with 5-ethynyl-2'-deoxyuridine being the most cytotoxic against L1210 cells.
D000480:Alkynes / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D007065:Idoxuridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D007939:Leukemia L1210 / Q000473:pathology; D051379:Mice; D011817:Rabbits; D018139:Simplexvirus / Q000187:drug effects; D013379:Substrate Specificity; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D014779:Virus Replication / Q000187:drug effects
D000480:Alkynes; D013940:Thymidylate Synthase; D007065:Idoxuridine