2'-azido-2',3'-dideoxypyrimidine nucleosides. Synthesis and antiviral activity against human immunodeficiency virus.
2'-azido-2',3'-dideoxypyrimidine nucleosides. Synthesis and antiviral activity against human immunodeficiency virus.
复制标题
2-叠氮基-2,3-二脱氧嘧啶核苷。
DOI：
10.1021/jm00168a020
复制
发表时间：
1990
影响因子：
7.3
通讯作者：
Watanabe,KA
中科院分区：
文献类型：
--
作者：
Warshaw,JA;Watanabe,KA
合成了4个2 ′-叠氮基-2 ′，3 ′-双脱氧嘧啶核苷类化合物，并研究了它们的抗人类免疫缺陷病毒活性。以5-O-苯甲酰基尿苷（5a）为原料，经咪唑硫代羰基化、Bu_3SnH还原，制得2，2 ′-脱水-5-O-苯甲酰基尿苷（6a）。用DMF中的LiN 3处理8a，然后皂化，得到2 ′-叠氮基-2 ′，3 ′-双脱氧尿苷（1a）。通过卤化和脱苯甲酰化将5 '-0-苯甲酰化核苷9a进一步转化为5-溴和5-碘类似物（Ib和Ic）。2 ′，3 ′-O-异亚丙基尿苷（3）经两步转化为胸腺嘧啶核苷，胸腺嘧啶核苷经苯甲酰化和脱-O-异亚丙基化得到5 ′-O-苯甲酰基-5-甲基尿苷（5d）。2 ′-叠氮基-2 ′，3 ′-二脱氧-5-甲基尿苷（Id）以与用于由5a合成Ia的类似的方式由5d合成。这些新的核苷类化合物与AZT密切相关，但在H9细胞培养中没有显示出明显的抗HIV活性，人类免疫缺陷病毒（HIV）已被证实为获得性免疫缺陷综合征（AIDS）的病原体。2核苷类似物，如3 '-叠氮基-3'-脱氧胸苷（AZT）3和其他2 '，3'-双脱氧核苷（DDN）4迄今为止在体外抗这种逆转录病毒最有效。虽然这些核苷类似物的确切作用机制尚未完全了解，但Furman等人5已表明，AZT可通过细胞酶转化为相应的三磷酸，这种三磷酸可作为HIV逆转录酶（RT）的竞争性抑制剂。此外，由于AZT三磷酸盐对逆转录酶的亲和力高于对细胞的亲和力，证明了RT的选择性抑制。
A series of four 2'-azido-2', 3'-dideoxypyrimidine nucleosides were synthesized and their activity against human immunodeficiency virus was explored. 2, 2'-Anhydro-5-0-benzoyluridine (6a) was prepared from 5-O-benzoyluridine (5a) and converted into 3'-deoxy analogue 8a by imidazolylthiocarbonylation followed by Bu3SnH reduction. Treatment of 8a with LiN3 in DMF followed by saponification afforded 2'-azido-2', 3'-dideoxyuridine (la). The 5'-0-benzoylated nucleoside 9a was further converted into the 5-bromo and 5-iodo analogues (lb and lc) by halogenation and debenzoylation. 2', 3'-0-Isopropylideneuridine (3) was converted in two steps into the thymine nucleoside, which was benzoylated and de-O-isopropylidenated to afford 5'-0-benzoyl-5-methyluridine (5d). 2'-Azido-2', 3'-dideoxy-5-methyluridine (Id) was synthesized from 5d in a similar manner as that used for the synthesis of la from 5a. These new nucleosides, closely related to AZT, however, did not exhibit any significant anti-HIV activity intissue culture using H9 cells.Human immunodeficiency virus (HIV) has been recog-nized as the etiologic agent of aquired immunodeficiency syndrome (AIDS). 2 Nucleoside analogues, such as 3'-azido-3'-deoxythymidine (AZT) 3 and other 2', 3'-dideoxy-nucleosides (DDN) 4 are thus far the most active against this retrovirus in vitro. Although the exact mechanism of action of these nucleoside analogues is not fully under-stood, Furman et al. 5 has shown that AZT is converted to its corresponding triphosphate by cellular enzymes and this triphosphate acts as a competitive inhibitor of the reverse transcriptase (RT) of HIV. In addition, selective inhibition of RT was demonstrated due to the higher affinity ofAZT triphosphate for the reverse transcriptase than for cellular