Synthesis and antiviral activity of various 3'-azido analogues of pyrimidine deoxyribonucleosides against human immunodeficiency virus (HIV-1, HTLV-III/LAV).
Synthesis and antiviral activity of various 3'-azido analogues of pyrimidine deoxyribonucleosides against human immunodeficiency virus (HIV-1, HTLV-III/LAV).
复制标题
嘧啶脱氧核糖核苷的各种 3-叠氮类似物的合成和抗人类免疫缺陷病毒（HIV-1、HTLV-III/LAV）的抗病毒活性。
DOI：
10.1021/jm00397a011
复制
发表时间：
1988
影响因子：
7.3
通讯作者：
Prusoff,WH
中科院分区：
文献类型：
--
作者：
Lin,TS;Guo,JY;Schinazi,RF;Chu,CK;Xiang,JN;Prusoff,WH
已经合成了多种嘧啶脱氧核糖核苷的3'-叠氮类似物，并在人外周血单核细胞中对人类免疫缺陷病毒（HIV-1, HTLV-III/LAV）进行了检测。在这些化合物中,3 '叠氮基的胸苷类似物(2),3 - (3-oxo-l-propenyl)胸苷(21),2》脱氧尿苷(1),2”-deoxy-5-bromouridine(5), 2》-deoxy-5-fluorocytidine(19), 2”-deoxy-5-iodouridine(6), 2》脱氧胞苷(18),2”-deoxy-5-fluorouridine (4), 2, -deoxy-5-thiocyanatouridine (16), 2, -deoxy-5-methylcytidine(20), 2》-deoxy-5-aminouridine(7),每天在家“-deoxy-5-hydroxyuridine(10)被发现有明显的抗病毒活性,EC50值为0.002,0.01,0.2,1.0,1.0,1.1,分别为1.2、4.8、5.1、5.1、6.2、10µ。讨论了构效关系。3'-叠氮-3'-脱氧胸腺嘧啶（AZT）被Mit-suya等人发现12是人类免疫缺陷病毒（HIV）复制的有效抑制剂，这被认为是导致临床综合征称为艾滋病的原因。Furman等人3研究了AZT的代谢，发现AZT被依次磷酸化为单磷酸、二磷酸和三磷酸类似物。作为三磷酸类似物，AZT抑制逆转录酶对dTTP的利用，并可能结合在DNA的末端位置，从而阻止延伸。在任何一种情况下，HIV-1 DNA的合成都被阻止，从而抑制HIV-1的复制。其他抑制部位也可能参与其中；然而，这一点尚未得到证实。Hartshorn等发现AZT与重组α - A干扰素联合使用对细胞培养中的HIV-1有协同抑制作用；4然而，当AZT与利巴韦林合用时，Vogt等5发现AZT具有拮抗作用。
Various 3'-azido analogues of pyrimidine deoxyribonucleosides havebeen synthesized and tested against human immunodeficiency virus (HIV-1, HTLV-III/LAV) in human peripheral blood mononuclear cells. Among these compounds, the 3'-azido analogues of thymidine (2), 3-(3-oxo-l-propenyl) thymidine (21), 2'-deoxyuridine (1), 2'-deoxy-5-bromouridine (5), 2'-deoxy-5-fluorocytidine (19), 2'-deoxy-5-iodouridine (6), 2'-deoxycytidine (18), 2'-deoxy-5-fluorouridine (4), 2,-deoxy-5-thiocyanatouridine (16), 2,-deoxy-5-methylcytidine (20), 2'-deoxy-5-aminouridine (7), and2'-deoxy-5-hydroxyuridine (10) were found to have signficant antiviral activity, with EC50 values of 0.002, 0.01, 0.2, 1.0, 1.0, 1.1, 1.2, 4.8, 5.1, 5.1, 6.2, and 10 µ, respectively. The structure-activity relationships are discussed.3'-Azido-3'-deoxythymidine (AZT) was found by Mit-suya et al. 1 2 to be a potent inhibitor of the replication of the human immunodeficiency virus (HIV), which is ac-cepted to be responsible for the clinical syndrome termed AIDS. Furman et al. 3 investigated the metabolism of AZT and found it to be sequentially phosphorylated to the'-mono-,-di-, and-triphosphate analogues. As the tri-phosphate analogue, AZT inhibits the utilization of dTTP by reverse transcriptase and may be incorporated in the terminal position of DNA, thereby preventing elongation. 3 In either event, the synthesis of HIV-1 DNA is prevented and hence inhibition of HIV-1 replication. Other sites of inhibition may also be involved; however, this has not been established. When AZT was combined with recombinant alpha A interferon, a synergistic inhibition of HIV-1 in cell culture was found by Hartshorn et al.; 4 however, when AZT was combined with ribavirin, Vogt et al. 5 found it was antagonistic.