Organic Chemistry, Department of Chemistry, Faculty of Mathematics, Informatics and Natural Sciences, Universität Hamburg, Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany.
Laboratory of Virology and Chemotherapy, Department of Microbiology and Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium.
J Med Chem. 2020 Oct 22;63(20):11990-12007. doi: 10.1021/acs.jmedchem.0c01294. Epub 2020 Oct 14.
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.
核苷逆转录酶抑制剂（NRTIs）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为其具有抗病毒活性的三磷酸核苷类似物代谢物。我们报告了一类新的核苷三磷酸类似物的合成与表征，其中包含取代γ-磷酸的 C-烷基膦酸酯部分。这些化合物通过在γ-膦酸酯上连接酰氧基苄基（酯）或烷氧基羰氧基苄基（碳酸酯）基团，转化为生物可逆修饰的亲脂性前药。由于酶触发的递药机制，这些化合物形成了具有高选择性的γ-C-（烷基）-核苷三磷酸类似物。后者在 CD4 T 淋巴细胞（CEM 细胞）提取物中非常稳定，它们是 HIV 逆转录酶的底物，而不是 DNA 聚合酶α、β和γ的底物。在抗病毒测定中，在 CEM/0 细胞中发现的前药具有极好的抗病毒活性，在 CEM/TK 细胞中完全保留。与母体核苷 d4T 相比，活性提高了 3 个对数级。
