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Lipophilic Triphosphate Prodrugs of Various Nucleoside Analogues.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-06-09 , DOI: 10.1021/acs.jmedchem.0c00358 Xiao Jia 1 , Dominique Schols 2 , Chris Meier 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-06-09 , DOI: 10.1021/acs.jmedchem.0c00358 Xiao Jia 1 , Dominique Schols 2 , Chris Meier 1
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The antiviral efficacy of many nucleoside analogues is strongly dependent on their intracellular activation by host cellular kinases to yield ultimately the bioactive nucleoside analogue triphosphates (NTP). The metabolic conversion of nucleoside analogues into their triphosphates often proceeds insufficiently. We developed a nucleoside triphosphate (NTP) delivery system (the TriPPPro approach), in which the γ-phosphate is covalently modified by two different biodegradable masking units, one is the acyloxybenzyl (AB) moiety and the other is the alkoxycarbonyloxybenzyl (ACB) group. Such compounds formed NTPs with high selectivity by an enzyme-triggered mechanism in human T-lymphocyte CEM cell extracts loosing first the AB moiety, followed by the ACB group. This enables the bypass of all steps of the intracellular phosphorylation. This approach was applied here to convert some modestly active or even inactive nucleoside analogues into powerful biologically active metabolites. Potent antiviral activity profiles were obtained depending on the lipophilicity of the TriPPPro-NTP prodrugs against HIV-1 and HIV-2 replication in cultures of infected wild-type CD4+ CEM T-cells and more importantly in thymidine kinase-deficient CD4+ T-cells (CEM/TK–). This TriPPPro strategy offers high potential for future antiviral and antitumoral chemotherapies.
中文翻译：
各种核苷类似物的亲脂三磷酸前药。
许多核苷类似物的抗病毒功效在很大程度上取决于宿主细胞激酶对它们的胞内活化作用，从而最终产生具有生物活性的核苷类似物三磷酸酯（NTP）。核苷类似物代谢转化为三磷酸酯的过程通常进行得不充分。我们开发了三磷酸核苷（NTP）递送系统（Tri PPPRO法），其中γ-磷酸盐被两个不同的可生物降解的掩蔽单元共价修饰，一个是酰氧基苄基（AB）部分，另一个是烷氧基羰氧基苄基（ACB）基团。这样的化合物通过酶触发的机制在人T淋巴细胞CEM细胞提取物中形成高选择性的NTP，首先失去AB部分，然后失去ACB基团。这使得能够绕过细胞内磷酸化的所有步骤。在此应用此方法将某些中等活性或什至无活性的核苷类似物转化为强大的生物活性代谢物。根据在感染的野生型CD4 +的培养物中针对HIV-1和HIV-2复制的Tri PPP ro-NTP前药的亲脂性，可以获得有效的抗病毒活性。CEM T细胞，更重要的是在缺乏胸苷激酶的CD4 + T细胞（CEM / TK –）中。这种Tri PPP ro策略为将来的抗病毒和抗肿瘤化学疗法提供了巨大的潜力。
更新日期：2020-07-09
中文翻译：
各种核苷类似物的亲脂三磷酸前药。
许多核苷类似物的抗病毒功效在很大程度上取决于宿主细胞激酶对它们的胞内活化作用，从而最终产生具有生物活性的核苷类似物三磷酸酯（NTP）。核苷类似物代谢转化为三磷酸酯的过程通常进行得不充分。我们开发了三磷酸核苷（NTP）递送系统（Tri PPPRO法），其中γ-磷酸盐被两个不同的可生物降解的掩蔽单元共价修饰，一个是酰氧基苄基（AB）部分，另一个是烷氧基羰氧基苄基（ACB）基团。这样的化合物通过酶触发的机制在人T淋巴细胞CEM细胞提取物中形成高选择性的NTP，首先失去AB部分，然后失去ACB基团。这使得能够绕过细胞内磷酸化的所有步骤。在此应用此方法将某些中等活性或什至无活性的核苷类似物转化为强大的生物活性代谢物。根据在感染的野生型CD4 +的培养物中针对HIV-1和HIV-2复制的Tri PPP ro-NTP前药的亲脂性，可以获得有效的抗病毒活性。CEM T细胞，更重要的是在缺乏胸苷激酶的CD4 + T细胞（CEM / TK –）中。这种Tri PPP ro策略为将来的抗病毒和抗肿瘤化学疗法提供了巨大的潜力。
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