Dideoxynucleosides as Potential Anti-AIDS Drugs

1999年，该实验室发现和开发的用于治疗艾滋病的抗逆转录病毒药物洛地诺辛[6-amino-9-(2，3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)-9H-purine)]因肝脏毒性而被美国食品和药物管理局停止I/II期临床试验。妇幼保健院目前感兴趣的是确定所报告的肝脏毒性是否是原料药中6-amino-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)9H-嘌呤(2-F-Ara-A)0.1-0.3%污染的结果。根据其结构的性质，2-F-Ara-A有望成为比洛地诺更好的细胞聚合酶底物几个数量级。对细胞聚合酶的影响，特别是对线粒体的影响，可以解释临床毒性。污染物的合成是为了帮助这些研究，5-三磷酸代谢物的合成目前正在进行中。在机制水平上，利用最近的三元复合体(RT-DNA-dNTP)的X射线结构对艾滋病毒逆转录酶(RT)的活性部位进行的构象研究有助于确定酪氨酸115在调节来核苷及其2-α-氟非对映异构体的抗逆转录病毒活性中的作用(生物化学，2000年，29,11205-11215)。由于4-C-α-乙炔-2-脱氧核苷对多药耐药HIV具有很高的活性，LMCH开始合成相应的2，3-二脱氧版本的这些核苷。选择胞嘧啶类似物作为第一靶点。外消旋类似物的合成接近完成，将对D-和L-异构体进行研究。完成并测试了一系列构象受限的3-氧代双环[3.1.0]己烷二脱氧核苷类似物，其中包括天然碱(A，C，T，G)的α-和β-异构体。未检测到抗逆转录病毒活性。然而，α-胞嘧啶类似物的不同寻常的细胞毒性将在NCI 60细胞系的抗肿瘤活性筛选中进行研究。艾滋病标题：作为逆转录酶抑制剂的氟二脱氧核苷治疗艾滋病。4-C-α-乙炔-2-脱氧核苷和3-氧双环[3.1.0]己烷二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.