Membrane permeable, bioreversibly modified Prodrugs of Nucleoside Diphosphate-γ-phosphonates.
Membrane permeable, bioreversibly modified Prodrugs of Nucleoside Diphosphate-γ-phosphonates.
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膜渗透性、生物可逆修饰的核苷二磷酸-γ-膦酸盐的前药
DOI：
10.1021/acs.jmedchem.0c01294
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发表时间：
2020
影响因子：
7.3
通讯作者：
Schols
中科院分区：
文献类型：
--
作者：
Schols
核苷逆转录酶抑制剂(NRTI)被广泛用作抗病毒和抗癌药物，尽管它们需要在细胞内磷酸化成其抗病毒活性形式，即三磷酸化的核苷类似物代谢物。我们报道了一类新的核苷三磷酸类似物的合成和表征，该类似物含有取代γ-磷酸的C-烷基-磷酸部分。这些化合物在γ-膦酸根上通过连接酰氧基苄基(酯)或烷氧基甲氧基苄基(碳酸酯)被转化为生物可逆修饰的亲脂前药。这些化合物形成了γ-C-(烷基)-核苷三磷酸类似物，由于酶触发的递送机制，具有高选择性。后一种化合物在CD_4~+T淋巴细胞(CEM细胞)提取液中非常稳定，它们是艾滋病毒逆转录酶的底物，而不是DNA聚合酶α，β和γ的底物。在抗病毒实验中，CEM/0细胞中发现的前药的良好抗病毒活性在CEM/TK-细胞中完全保持。与亲本核苷d4T相比，活性提高了3个对数。
Nucleoside reverse transcriptase inhibitors (NRTIs) are widely used as antiviral and anticancer agents, although they require intracellular phosphorylation into their antivirally active form, the triphosphorylated nucleoside analogue metabolites. We report on the synthesis and characterization of a new class of nucleoside triphosphate analogues comprising a C-alkyl-phosphonate moiety replacing the γ-phosphate. These compounds were converted into bioreversibly modified lipophilic prodrugs at the γ-phosphonate by the attachment of an acyloxybenzyl (ester) or an alkoxycarbonyloxybenzyl (carbonate) group. Such compounds formed γ-C-(alkyl)-nucleoside triphosphate analogues with high selectivity because of an enzyme-triggered delivery mechanism. The latter compounds were very stable in CD4+T-lymphocyte (CEM cell) extracts, and they were substrates for HIV-reverse transcriptase without being substrates for DNA-polymerases α, β, and γ. In antiviral assays, the excellent antiviral activity of the prodrugs that was found in CEM/0 cells was completely kept in CEM/TK–cells. The activity was improved by 3 logs as compared to the parent nucleoside d4T.
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DOI：
10.1016/s0021-9258(18)83322-1
发表时间：
1989-04
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
J. Balzarini;P. Herdewijn;E. Clercq
通讯作者：
J. Balzarini;P. Herdewijn;E. Clercq
叔丁基-N-氯氰酰胺：一种新型多功能有机合成试剂
DOI：
--
发表时间：
2007
期刊：
影响因子：
--
作者：
Vinod Kumar;M. P. Kaushik
通讯作者：
M. P. Kaushik
使用亲脂性胆固醇衍生物跨膜运输 5-三磷酸腺苷。
影响因子：
--
作者：
A. Kreimeyer;F. André;C. Gouyette;T. Huynh
通讯作者：
T. Huynh
3-叠氮基-3-脱氧胸苷 (AZT) 单磷酸盐：AZT 末端 DNA 核酸外切修复的抑制剂
影响因子：
4.9
作者：
J. Harrington;J. Reardon;T. Spector
通讯作者：
T. Spector
影响因子：
5.8
作者：
BALZARINI, J;PAUWELS, R;JOHNS, DG
通讯作者：
JOHNS, DG