生物活性核苷的侧链衍生物。1. 3'-叠氮基-3'-脱氧胸苷（AZT）的侧链类似物。
Side-chain derivatives of biologically active nucleosides. 1. Side-chain analogs of 3'-azido-3'-deoxythymidine (AZT).
作者信息
Hiebl J, Zbiral E, Balzarini J, De Clercq E
机构信息
Institut für Organische Chemie, Universität Wien, Austria.
出版信息
J Med Chem. 1992 Aug 7;35(16):3016-23. doi: 10.1021/jm00094a014.
Starting from 3-O-mesyl-1,2-O-isopropylidene-alpha-D-allofuranose (9) the anomeric mixtures of the requisite carbohydrates 1,2-di-O-acetyl-6-O-benzoyl-5-deoxy-3-O-mesyl-D-allofuranoses++ + 17A alpha/beta, 1,2-di-O-acetyl-5,6-di-O-benzoyl-3-O-mesyl-D-allofuranoses 17B alpha/beta, and 1,2-di-O-acetyl-5,6-di-O-benzoyl-3-O-mesyl-L-talofuranoses 17C alpha/beta were synthesized. 1,2-Di-O-acetyl-5-O-benzoyl-6-deoxy-3-O-mesyl-D-allofuranoses++ + 17D alpha/beta and the corresponding L-talofuranoses 17E alpha/beta were obtained from 6-deoxy-3,5-di-O-benzoyl-1,2-O-isopropylidene-alpha-D- allofuranose (12) and the corresponding beta-L-talofuranose 13. Coupling of these sugar derivatives with thymine gave the beta-nucleoside derivatives 18A-E. Treatment of compounds 18A-E with DBU produced the corresponding 2,3'-anhydro nucleosides 19A-E with a free 2'-OH group. After deoxygenation of 2'-O-[[(4-methylphenyl)oxy]thiocarbonyl] compounds 20A-E with tributyltin hydride the 2,3'-anhydro bridge of the 2'-deoxynucleosides 21A-E was opened with LiN3 to produce the protected 3'-azido-2,3'-dideoxynucleoside derivatives 22A-G. Saponification with NaOCH3 gave 1-(3'-azido-2',3',5'-trideoxy-beta-D-allofuranosyl)thymine (2; homo-AZT), the 5'-C-(hydroxymethyl) derivatives of AZT 1-(3'-azido-2',3'- dideoxy-beta-D-allofuranosyl)thymine (3) and 1-(3'-azido-2',3'-dideoxy-alpha-L-talofuranosyl)thymine (4), and the 5'-C-methyl derivatives of AZT 1-(3'-azido-2',3',6'-trideoxy-beta-D-allofuranosyl)thymine (5) and 1-(3'-azido-2',3',6'-trideoxy-alpha-L-talofuranosyl)thymine (6). Compounds 2-6 were evaluated for their inhibitory effect on human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) replication in MT-4 cells and found inactive at subtoxic concentrations. Compounds 2-4 and 6 are not effective against herpes simplex virus type 1 (HSV-1) and type 2 (HIV-2), vaccinia virus (VV), and vesicular stomatitis virus (VSV) at 400 micrograms/mL. 5 is slightly active against HSV-1, HSV-2 and VV at 150, 300, and 300 micrograms/mL, respectively.
从3 - O - 甲磺酰基 - 1,2 - O - 异亚丙基 - α - D - 阿洛呋喃糖（9）开始，合成了所需碳水化合物的异头物混合物，即1,2 - 二 - O - 乙酰基 - 6 - O - 苯甲酰基 - 5 - 脱氧 - 3 - O - 甲磺酰基 - D - 阿洛呋喃糖++ + 17Aα/β、1,2 - 二 - O - 乙酰基 - 5,6 - 二 - O - 苯甲酰基 - 3 - O - 甲磺酰基 - D - 阿洛呋喃糖17Bα/β以及1,2 - 二 - O - 乙酰基 - 5,6 - 二 - O - 苯甲酰基 - 3 - O - 甲磺酰基 - L - 塔罗呋喃糖17Cα/β。1,2 - 二 - O - 乙酰基 - 5 - O - 苯甲酰基 - 6 - 脱氧 - 3 - O - 甲磺酰基 - D - 阿洛呋喃糖++ + 17Dα/β以及相应的L - 塔罗呋喃糖17Eα/β是由6 - 脱氧 - 3,5 - 二 - O - 苯甲酰基 - 1,2 - O - 异亚丙基 - α - D - 阿洛呋喃糖（12）和相应的β - L - 塔罗呋喃糖13制得。这些糖衍生物与胸腺嘧啶偶联得到β - 核苷衍生物18A - E。用DBU处理化合物18A - E得到相应的具有游离2'-OH基团的2,3'-脱水核苷19A - E。用三丁基氢化锡对2'-O - [[(4 - 甲基苯基)氧基]硫代羰基]化合物20A - E进行脱氧后，用LiN₃打开2'-脱氧核苷21A - E的2,3'-脱水桥，得到受保护的3'-叠氮基 - 2,3'-二脱氧核苷衍生物22A - G。用NaOCH₃进行皂化反应得到1 - (3'-叠氮基 - 2',3',5'-三脱氧 - β - D - 阿洛呋喃糖基)胸腺嘧啶（2；同型齐多夫定）、齐多夫定的5'-C - (羟甲基)衍生物1 - (3'-叠氮基 - 2',3'-二脱氧 - β - D - 阿洛呋喃糖基)胸腺嘧啶（3）和1 - (3'-叠氮基 - 2',3'-二脱氧 - α - L - 塔罗呋喃糖基)胸腺嘧啶（4），以及齐多夫定的5'-C - 甲基衍生物1 - (3'-叠氮基 - 2',3',6'-三脱氧 - β - D - 阿洛呋喃糖基)胸腺嘧啶（5）和1 - (3'-叠氮基 - 2',3',6'-三脱氧 - α - L - 塔罗呋喃糖基)胸腺嘧啶（6）。对化合物2 - 6在MT - 4细胞中对人免疫缺陷病毒1型（HIV - 1）和2型（HIV - 2）复制的抑制作用进行了评估，发现在亚毒性浓度下无活性。化合物2 - 4和6在400微克/毫升时对单纯疱疹病毒1型（HSV - 1）和2型（HIV - 2）、痘苗病毒（VV）以及水疱性口炎病毒（VSV）无效。5在150、300和300微克/毫升时分别对HSV - 1、HSV - 2和VV有轻微活性。
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