Minakawa N, Takeda T, Sasaki T, Matsuda A, Ueda T
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
J Med Chem. 1991 Feb;34(2):778-86. doi: 10.1021/jm00106a045.
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.
在含有三乙胺的乙腈中，5-碘-1-(2,3,5-三-O-乙酰基-β-D-呋喃核糖基)咪唑-4-甲酰胺(8)与各种末端炔烃在二氯双(苄腈)钯存在下进行钯催化的交叉偶联反应，以高产率得到所需的5-炔基衍生物9。然而，当使用(三甲基硅基)乙炔时，唯一可分离的产物是不需要的二聚体，1,2-双(4-氨基甲酰基-1-β-D-呋喃核糖基咪唑-5-基)乙炔衍生物10a。为了避免这种二聚体的形成，反应在没有三乙胺的情况下使用三甲基-[(三丁基锡基)乙炔基]硅烷进行，以良好的产率得到所需的5-(2-三甲基硅基)乙炔基衍生物9a。此外，5-碘-1-(2,3,5-三-O-乙酰基-β-D-呋喃核糖基)咪唑-4-甲腈(12)与(三甲基硅基)乙炔的类似交叉偶联反应也得到了所需的核苷13a。这些化合物脱保护得到5-炔基-1-β-D-呋喃核糖基咪唑-4-甲酰胺(6b-k)和-甲腈(14b-f)。其中，5-乙炔基-1-β-D-呋喃核糖基咪唑-4-甲酰胺(6b，EICAR)是培养的各种肿瘤细胞包括人实体瘤细胞生长的最有效抑制剂。还描述了对小鼠白血病L1210和P388的体内抗肿瘤活性的初步结果。
