The design, synthesis and antileukemic activity of 5-alkynyl-1-β-D-ribofuranosylimidazole-4-carboxamides1

Abstract

The design, synthesis and antileukemic activity of 5-alkynyl-1-β-D-ribofuranosylimidazole-4-carboxamides (6) are described. The cross-coupling reaction of 5-iodo-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)imidazole-4-carboxamide (8) with various terminal alkynes in the presence of bis(benzonitrile)palladium dichloride and triethylamine in acetonitrile gave 5-alkynyl derivatives (9) in high yields. Coupling of 8 with (trimethylsilyl)acetylene gave the undesired dimer (10). Instead of (trimethylsilyl)acetylene, treatment of trimethyl[(tributyl-stannyl)ethynyl]silane with 8 in the absence of triethylamine produced the desired 5-[2-(trimethylsilyl)ethynyl] derivative (9f) in 77% yield. Deblocking of these nucleosides (9) gave the target nucleosides (6a-f). Among them, 5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide (6f) is the most potent inhibitor of the growth of murine L1210 cells in vitro (IC50=0.18μg/ml). © 1988, The Pharmaceutical Society of Japan. All rights reserved.