Dideoxynucleosides as Potential Anti-AIDS Drugs

1999年，在本实验室发现并开发的用于治疗艾滋病的抗逆转录病毒药物碘腺苷[6-氨基-9-（2，3-二脱氧-2-氟-β-D-苏-戊呋喃糖基）-9H-嘌呤]因肝毒性而被FDA从I/II期临床试验中终止。 LMCH目前有兴趣确定报告的肝毒性是否是原料药被6-氨基-（2-脱氧-2-氟-β-D-阿拉伯呋喃糖基）9 H-嘌呤（2-F-ara-A）污染0.1 0.3%的结果。由于其结构的性质，2-F-ara-A预期是比碘腺苷好几个数量级的细胞聚合酶底物。对细胞聚合酶的影响，特别是来自线粒体的影响，可以解释临床毒性。污染物的合成有助于这些研究，5-三磷酸代谢物的合成目前正在进行中。在机理水平上，利用三元复合物（RT-DNA-dNTP）的最新X射线结构对HIV逆转录酶（RT）的活性位点的构象研究有助于确定酪氨酸115在调节碘腺苷及其2-α-氟非对映异构体的抗逆转录病毒活性中的作用（Biochemistry 2000，29，11205-11215）。在发现4-C-alpha-乙炔基-2-脱氧核苷对多药耐药HIV具有高度活性后，LMCH开始合成这些核苷的相应2，3-双脱氧形式。选择胞嘧啶类似物作为第一靶标。外消旋类似物的合成已接近完成，将对D-和L-异构体进行研究。 完成并测试了一系列新的构象受限的3-氧代双环[3.1.0]己烷双脱氧核苷类似物，其包含天然碱基（A，C，T，G）的α-和β-端基异构体。 未检测到抗逆转录病毒活性。然而，将在NCI 60细胞系抗肿瘤活性筛选中研究α-胞嘧啶类似物的异常细胞毒性。艾滋病标题：氟二脱氧核苷作为逆转录酶抑制剂用于治疗艾滋病。4-C-α-乙炔基-2-脱氧核苷和3-氧代双环[3.1.0]己烷双脱氧核苷作为抗逆转录病毒治疗的新模板。

In 1999, lodenosine [6-amino-9-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)-9H-purine)] , an antiretroviral agent discovered and developed in this laboratory for the treatment ofAIDS was discontinued from phase I/II clinical trials by the FDA due to liver toxicity. The LMCH is currently interested in determining whether the liver toxicity reported was the result of a 0.1 0.3% contamination of the bulk drug with 6-amino-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) 9H-purine (2-F-ara-A). By the nature of its structure, 2-F-ara-A is expected to be several orders of magnitude better substrate than lodenosine for cellular polymerases. The effect on cellular polymerases, particularly from mitochondria, could explain the clinical toxicity. The synthesis of the contaminant was performed to help with these studies and the synthesis of the 5-triphosphate metabolite is currently in progress. At the mechanistic level, a conformational study of the active site of HIV reverse transcriptase (RT) utilizing the recent X-ray structure of the ternary complex (RT-DNA-dNTP) helped define the role of Tyrosine 115 in modulating the antiretroviral activity of lodenosine and its 2-alpha-fluoro diastereoisomer (Biochemistry 2000, 29, 11205-11215). Following the lead that 4-C-alpha-ethynyl-2-deoxynucleosides are highly active against multi drug resistant HIV, the LMCH embarked in the synthesis of the corresponding 2,3-dideoxy version of these nucleosides. The cytosine analogue was selected as the first target. The synthesis of the racemic analogue is nearing completion, and both D- and L-isomers will be investigated. A novel series of conformationally constrained 3-oxobicyclo[3.1.0]hexane dideoxynucleoside analogues that comprised both alpha- and beta-anomers of the natural bases (A, C, T, G) was completed and tested. No antiretroviral activity was detected. However, the unusual cytotoxicity of the alpha-cytosine analogue will be investigated in the NCI 60 cell line screen for antitumor activity. AIDS title: Fluorodideoxynucleosides as reverse transcriptase inhibitors for the treatment of AIDS. 4-C-alpha-ethynyl-2-deoxynucleosides and 3-oxobicyclo[3.1.0]hexane dideoxynucleosides as novel templates for antiretroviral therapy.