Bamford M J, Coe P L, Walker R T
School of Chemistry, University of Birmingham, Edgbaston, England.
J Med Chem. 1990 Sep;33(9):2494-501. doi: 10.1021/jm00171a025.
A series of 3'-branched-chain sugar nucleosides, in particular 3'-deoxy-3'-C-hydroxmethyl nucleosides, have been synthesized and evaluated as antiviral agents. Reaction of 1-(2,3-epoxy-5-O-trityl-beta-D-lyxo-pentofuranosyl) derivatives 12 and 13, of uracil and thymine, respectively, with 5,6-dihydro-2-lithio-5-methyl-1,3,5-dithiazine 14 afforded the corresponding 3'-functionalized nucleosides 15 and 16, respectively. Replacement of the trityl group with tertbutyldiphenylsilyl allowed high yielding hydrolysis of the 3'-function to give the 3'-deoxy-3'-C-formyl-beta-D-arabino-pentofuranosyl nucleosides 21 and 22. Desilylation afforded the 1-(3-deoxy-3-C-formyl-beta- D-lyxo-pentofuranosyl) 3',5'-O-hemiacetal nucleosides 33 and 34, respectively. Reduction of the formyl group of 21 and 22, followed by desilylation, yielded the 3'-deoxy-3'-C-(hydroxymethyl)-beta-D-arabino- pentofuranosyl) analogues 7 and 8, respectively. The uracil base moiety of 7 was converted to 5-iodouracil and then to (E)-5-(2-bromovinyl)uracil to furnish an analogue 10 of BVaraU. The 1-(3-deoxy-3-C-(hydroxymethyl)-beta-D-lyxo-pentofuranosyl) and 1-(2,3-dideoxy-3-C-(hydroxymethyl)-beta-D-erythro-pentofuranosyl) derivatives of uracil (31 and 6, respectively) and 5-iodouracil (32 and 9, respectively) were also obtained. All novel, fully deprotected nucleoside analogues were evaluated for antiviral activity against human immunodeficiency virus type-1, herpes simplex virus types-1 and -2, varicella zoster virus, human cytomegalovirus and influenza A. Of the compounds tested only (E)-5-(2-bromovinyl)-1-[3-deoxy- 3-C-(hydroxymethyl)-beta-D-arabino-pentofuranosyl]uracil (10) inhibited VZV (alone), but did so at concentrations well below the cytotoxicity threshold.
已合成了一系列3'-支链糖核苷，特别是3'-脱氧-3'-C-羟甲基核苷，并将其作为抗病毒剂进行了评估。尿嘧啶和胸腺嘧啶的1-(2,3-环氧-5-O-三苯甲基-β-D-吡喃戊糖基)衍生物12和13分别与5,6-二氢-2-锂代-5-甲基-1,3,5-二噻嗪14反应，分别得到相应的3'-官能化核苷15和16。用叔丁基二苯基甲硅烷基取代三苯甲基可使3'-官能团高产率水解，得到3'-脱氧-3'-C-甲酰基-β-D-阿拉伯吡喃戊糖基核苷21和22。脱硅反应分别得到1-(3-脱氧-3-C-甲酰基-β-D-吡喃戊糖基)3',5'-O-半缩醛核苷33和34。21和22的甲酰基还原，然后脱硅，分别得到3'-脱氧-3'-C-(羟甲基)-β-D-阿拉伯吡喃戊糖基类似物7和8。7的尿嘧啶碱基部分转化为5-碘尿嘧啶，然后转化为(E)-5-(2-溴乙烯基)尿嘧啶，得到BVaraU的类似物10。还得到了尿嘧啶(分别为31和6)和5-碘尿嘧啶(分别为32和9)的1-(3-脱氧-3-C-(羟甲基)-β-D-吡喃戊糖基)和1-(2,3-二脱氧-3-C-(羟甲基)-β-D-赤藓吡喃戊糖基)衍生物。对所有新型的、完全脱保护的核苷类似物进行了抗人类免疫缺陷病毒1型、单纯疱疹病毒1型和2型、水痘带状疱疹病毒、人巨细胞病毒和甲型流感病毒活性的评估。在测试的化合物中，只有(E)-5-(2-溴乙烯基)-1-[3-脱氧-3-C-(羟甲基)-β-D-阿拉伯吡喃戊糖基]尿嘧啶(10)能单独抑制水痘带状疱疹病毒，但抑制浓度远低于细胞毒性阈值。
