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γ-Ketobenzyl-Modified Nucleoside Triphosphate Prodrugs as Potential Antivirals
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-11-13 , DOI: 10.1021/acs.jmedchem.0c01293 Tobias Nack 1 , Thiago Dinis de Oliveira 1 , Stefan Weber 1 , Dominique Schols 2 , Jan Balzarini 2 , Chris Meier 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-11-13 , DOI: 10.1021/acs.jmedchem.0c01293 Tobias Nack 1 , Thiago Dinis de Oliveira 1 , Stefan Weber 1 , Dominique Schols 2 , Jan Balzarini 2 , Chris Meier 1
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The antiviral activity of nucleoside reverse transcriptase inhibitors is often hampered by insufficient phosphorylation. Nucleoside triphosphate analogues are presented, in which the γ-phosphate was covalently modified by a non-bioreversible, lipophilic 4-alkylketobenzyl moiety. Interestingly, primer extension assays using human immunodeficiency virus reverse transcriptase (HIV-RT) and three DNA-polymerases showed a high selectivity of these γ-modified nucleoside triphosphates to act as substrates for HIV-RT, while they proved to be nonsubstrates for DNA-polymerases α, β, and γ. In contrast to d4TTP, the γ-modified d4TTPs showed a high resistance toward dephosphorylation in cell extracts. A series of acyloxybenzyl-prodrugs of these γ-ketobenzyl nucleoside triphosphates was prepared. The aim was the intracellular delivery of a stable γ-modified nucleoside triphosphate to increase the selectivity of such compounds to act in infected versus noninfected cells. Delivery of γ-ketobenzyl-d4TTPs was proven in T-lymphocyte cell extracts. The prodrugs were potent inhibitors of HIV-1/2 in cultures of infected CEM/0 cells and more importantly in thymidine kinase-deficient CD4+ T-cells.
中文翻译：
γ-酮苄基修饰的核苷三磷酸前药作为潜在的抗病毒药
核苷逆转录酶抑制剂的抗病毒活性通常受到磷酸化不足的阻碍。提出了核苷三磷酸酯类似物，其中γ-磷酸酯被非生物可逆的亲脂性4-烷基酮苄基部分共价修饰。有趣的是，使用人类免疫缺陷病毒逆转录酶（HIV-RT）和三种DNA聚合酶进行引物延伸分析显示，这些γ-修饰的核苷三磷酸作为HIV-RT的底物具有很高的选择性，而事实证明它们不是DNA-的非底物。聚合酶α，β和γ。与d4TTP相比，γ-修饰的d4TTP在细胞提取物中表现出对去磷酸化的高抗性。制备了这些γ-酮苄基核苷三磷酸的一系列酰氧基苄基前药。目的是在细胞内递送稳定的γ-修饰的三磷酸核苷，以增加此类化合物在感染细胞与未感染细胞中起作用的选择性。γ-酮苄基-d4TTP的传递已在T淋巴细胞细胞提取物中得到证实。在感染的CEM / 0细胞培养物中，前药是有效的HIV-1 / 2抑制剂，更重要的是在胸苷激酶缺陷型CD4中+ T细胞。
更新日期：2020-11-25
中文翻译：
γ-酮苄基修饰的核苷三磷酸前药作为潜在的抗病毒药
核苷逆转录酶抑制剂的抗病毒活性通常受到磷酸化不足的阻碍。提出了核苷三磷酸酯类似物，其中γ-磷酸酯被非生物可逆的亲脂性4-烷基酮苄基部分共价修饰。有趣的是，使用人类免疫缺陷病毒逆转录酶（HIV-RT）和三种DNA聚合酶进行引物延伸分析显示，这些γ-修饰的核苷三磷酸作为HIV-RT的底物具有很高的选择性，而事实证明它们不是DNA-的非底物。聚合酶α，β和γ。与d4TTP相比，γ-修饰的d4TTP在细胞提取物中表现出对去磷酸化的高抗性。制备了这些γ-酮苄基核苷三磷酸的一系列酰氧基苄基前药。目的是在细胞内递送稳定的γ-修饰的三磷酸核苷，以增加此类化合物在感染细胞与未感染细胞中起作用的选择性。γ-酮苄基-d4TTP的传递已在T淋巴细胞细胞提取物中得到证实。在感染的CEM / 0细胞培养物中，前药是有效的HIV-1 / 2抑制剂，更重要的是在胸苷激酶缺陷型CD4中+ T细胞。
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