Adenosine Dioxolane Nucleoside Phosphoramidates as Antiviral Agents for Human Immunodeficiency and Hepatitis B Viruses.
Adenosine Dioxolane Nucleoside Phosphoramidates as Antiviral Agents for Human Immunodeficiency and Hepatitis B Viruses.
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腺苷二氧戊环核苷氨基磷酸酯作为人类免疫缺陷和乙型肝炎病毒的抗病毒剂。
DOI：
10.1021/ml4001497
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发表时间：
2013
影响因子：
4.2
通讯作者：
Schinazi,RaymondF
中科院分区：
文献类型：
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作者：
Bondada,Lavanya;Detorio,Mervi;Bassit,Leda;Tao,Sijia;Montero,CatherineM;Singletary,TyanaM;Zhang,Hongwang;Zhou,Longhu;Cho,Jong-Hyun;Coats,StevenJ;Schinazi,RaymondF
目前有六种核苷逆转录酶抑制剂（NRTI）被FDA批准用于人类临床使用，这些仍然是目前HIV治疗的支柱。为了使这些NRTI有效，它们需要被细胞激酶连续磷酸化为它们的三磷酸形式。在此，我们报告了C-6修饰的（−）-β-d-（2 R，4 R）-1，3-二氧戊环腺苷核苷及其核苷酸的合成，包括我们的新型氨基磷酸酯前药技术。我们已经在氨基磷酸酯的苯酚部分上引入了侧链部分以降低潜在毒性。合成的氨基磷酸酯显示出高达3600倍更大的效力对HIV-1相比，其相应的母体核苷和高达300倍更有效地对HBV。在所测试的各种细胞系统中，除了化合物17和18（其在Huh-7细胞中分别显示出7.3和12 μM的CC 50）之外，在高达100 μM的浓度下未观察到细胞毒性。这些新的氨基磷酸酯核苷的改善的和显著的双重抗病毒活性部分地由腺苷二氧戊环三磷酸的细胞内形成的增加来解释。
There are currently six nucleoside reverse transcriptase inhibitors (NRTI) that are FDA approved for human clinical use and these remain the backbone of current HIV therapy. In order for these NRTIs to be effective they need to be phosphorylated consecutively by cellular kinases to their triphosphate forms. Herein, we report the synthesis of C-6 modified (−)-β-d-(2R,4R)-1,3-dioxolane adenosine nucleosides and their nucleotides including our novel phosphoramidate prodrug technology. We have introduced a side chain moiety on the phenol portion of the phosphoramidate to reduce the toxicity potential. The synthesized phosphoramidates displayed up to a 3600-fold greater potency versus HIV-1 when compared to their corresponding parent nucleoside and were up to 300-fold more potent versus HBV. No cytotoxicity was observed up to 100 μM in the various cell systems tested, except for compounds17and18, which displayed a CC50of 7.3 and 12 μM, respectively, in Huh-7 cells. The improved and significant dual antiviral activity of these novel phosphoramidate nucleosides was partially explained by the increased intracellular formation of the adenosine dioxolane triphosphate.