The
palladium-catalyzed cross-coupling reaction of 5-iodo-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)imidazole-4- carboxamide (8) with various terminal
alkynes in the presence of bis(
benzonitrile)
palladium dichloride in
acetonitrile containing
triethylamine gave the desired 5-alkynyl derivatives 9 in high yields. However, when (trimethylsilyl)
acetylene was used, the only isolable product was the undesired dimer, 1,2-bis(4-carbamoyl-1-beta-D-ribofuranosylimidazol-5-yl)acetylene derivative 10a. To circumvent such dimer formation, the reaction was done with use of trimethyl-[(tributylstannyl)ethynyl]
silane in the absence of
triethylamine to afford the desired 5-(2-trimethylsilyl)ethynyl derivative 9a in good yield. Furthermore, the similar cross-coupling reaction of 5-iodo-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)imidazole-4-carboni tri le (12) with (trimethylsilyl)
acetylene also afforded the desired
nucleoside 13a. Deprotection of these compounds furnished 5-alkynyl-1-beta-D-ribofuranosylimidazole-4-carboxamides (6b-k) and -carbonitriles (14b-f). Among these, 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide (6b,
EICAR) is the most potent inhibitor of growth of the various
tumor cells in culture including human solid
tumor cells. Preliminary results of in vivo antitumor activity against murine
leukemias L1210 and P388 are also described.