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.