Gudmundsson K S, Drach J C, Wotring L L, Townsend L B
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor 49019-1065, USA.
J Med Chem. 1997 Feb 28;40(5):785-93. doi: 10.1021/jm9604888.
A series of 5'-modified 2,5,6-trichlorobenzimidazole ribonucleosides has been synthesized and tested for activity against two human herpesviruses and for cytotoxicity. The 5'-methoxy, 5'-ethoxy, and 5'-butoxy analogs of 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB) were prepared by coupling the appropriate 5-O-alkyl-1,2,3-tri-O-acetyl-beta-D-ribose derivatives with 2,5,6-trichlorobenzimidazole followed by removal of the protecting groups. The 5'-deoxy-5'-fluoro, -5'-chloro, -5'-bromo, -5'-iodo, -5'-azido, and -5'-thiomethyl derivatives were synthesized in a similar fashion. All of these 5'-modified derivatives had significant activity against HCMV in plaque and yield reduction assays (IC50's = 0.5-14.2 microM) but had little activity (IC50's > 100 microM) against HSV-1. This pattern in similar to the antiviral activity profile observed for TCRB. The 5'-halogenated derivatives were more active than the other 5'-modified derivatives with antiviral activity well separated from cytotoxicity. In general, cytotoxicity of all the 5'-modified derivatives was greater in human foreskin fibroblasts (HFF cells) than in L1210 or KB tumor cells. These results indicate that the viral target tolerates significant modifications of TCRB at the 5'-position without adversely affecting activity against HCMV, whereas the 5'-modifications increased cytotoxicity in human diploid cells.
已合成了一系列5'-修饰的2,5,6-三氯苯并咪唑核糖核苷，并测试了它们对两种人类疱疹病毒的活性和细胞毒性。通过将适当的5-O-烷基-1,2,3-三-O-乙酰基-β-D-核糖衍生物与2,5,6-三氯苯并咪唑偶联，然后除去保护基团，制备了2,5,6-三氯-1-(β-D-呋喃核糖基)苯并咪唑(TCRB)的5'-甲氧基、5'-乙氧基和5'-丁氧基类似物。5'-脱氧-5'-氟、-5'-氯、-5'-溴、-5'-碘、-5'-叠氮基和-5'-硫代甲基衍生物以类似方式合成。所有这些5'-修饰的衍生物在蚀斑和产量降低试验中对人巨细胞病毒(HCMV)具有显著活性(IC50 = 0.5-14.2 microM)，但对单纯疱疹病毒1型(HSV-1)几乎没有活性(IC50 > 100 microM)。这种模式与观察到的TCRB的抗病毒活性谱相似。5'-卤代衍生物比其他5'-修饰的衍生物更具活性，其抗病毒活性与细胞毒性有很好的区分。一般来说，所有5'-修饰衍生物在人包皮成纤维细胞(HFF细胞)中的细胞毒性比在L1210或KB肿瘤细胞中更大。这些结果表明，病毒靶点能够耐受TCRB在5'-位的显著修饰，而不会对针对HCMV的活性产生不利影响，而5'-修饰增加了人二倍体细胞中的细胞毒性。
