title: Nucleosides and nucleotides. 96. Synthesis and antitumor activity of 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide (EICAR) and its derivatives.
abstract: 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.
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Minakawa
authors.forename: T
authors.initials: T
authors.lastname: Takeda
authors.forename: T
authors.initials: T
authors.lastname: Sasaki
authors.forename: A
authors.initials: A
authors.lastname: Matsuda
authors.forename: T
authors.initials: T
authors.lastname: Ueda
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D002460:Cell Line; D055598:Chemical Phenomena; D002621:Chemistry; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D012263:Ribonucleosides / Q000138:chemical synthesis* / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D012263:Ribonucleosides; C059077:5-ethynyl-1-ribofuranosylimidazole-4-carboxamide