2'-脱氧-2'-氟-2'-C-甲基-7-脱氮嘌呤核苷及其磷酰胺酸酯前药和 5'-三磷酸酯的合成及抗病毒活性。
Synthesis and antiviral activity of 2'-deoxy-2'-fluoro-2'-C-methyl-7-deazapurine nucleosides, their phosphoramidate prodrugs and 5'-triphosphates.
机构信息
RFS Pharma, LLC, 1860 Montreal Road, Tucker, GA 30084, USA.
出版信息
Bioorg Med Chem Lett. 2011 Dec 1;21(23):7094-8. doi: 10.1016/j.bmcl.2011.09.089. Epub 2011 Sep 29.
Abstract
Thirty novel α- and β-d-2'-deoxy-2'-fluoro-2'-C-methyl-7-deazapurine nucleoside analogs were synthesized and evaluated for in vitro antiviral activity. Several α- and β-7-deazapurine nucleoside analogs exhibited modest anti-HCV activity and cytotoxicity. Four synthesized 7-deazapurine nucleoside phosphoramidate prodrugs (18-21) showed no anti-HCV activity, whereas the nucleoside triphosphates (22-24) demonstrated potent inhibitory effects against both wild-type and S282T mutant HCV polymerases. Cellular pharmacology studies in Huh-7 cells revealed that the 5'-triphosphates were not formed at significant levels from either the nucleoside or the phosphoramidate prodrugs, indicating that insufficient phosphorylation was responsible for the lack of anti-HCV activity. Evaluation of anti-HIV-1 activity revealed that an unusual α-form of 7-carbomethoxyvinyl substituted nucleoside (10) had good anti-HIV-1 activity (EC(50)=0.71±0.25 μM; EC(90)=9.5±3.3 μM) with no observed cytotoxicity up to 100 μM in four different cell lines.
摘要
合成了 30 种新型的α-和β-D-2'-脱氧-2'-氟-2'-C-甲基-7-脱氮嘌呤核苷类似物，并评估了它们的体外抗病毒活性。几种α-和β-7-脱氮嘌呤核苷类似物表现出中等的抗 HCV 活性和细胞毒性。合成的 4 种 7-脱氮嘌呤核苷膦酰胺前药（18-21）没有抗 HCV 活性，而核苷三磷酸（22-24）对野生型和 S282T 突变 HCV 聚合酶均显示出很强的抑制作用。在 Huh-7 细胞中的细胞药理学研究表明，无论是核苷还是膦酰胺前药，5'-三磷酸均未在显著水平上形成，这表明磷酸化不足是导致缺乏抗 HCV 活性的原因。抗 HIV-1 活性评估表明，一种不寻常的 7-羧甲氧基乙烯基取代核苷的α-形式（10）具有良好的抗 HIV-1 活性（EC(50)=0.71±0.25 μM；EC(90)=9.5±3.3 μM），在四种不同的细胞系中，在高达 100 μM 的浓度下没有观察到细胞毒性。
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