Organic Chemistry, Department of Chemistry, Faculty of Sciences, Universität Hamburg, Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany.
Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium.
J Med Chem. 2022 Sep 22;65(18):12163-12175. doi: 10.1021/acs.jmedchem.2c00665. Epub 2022 Sep 13.
3'-Fluoro-3'-deoxythymidine (FLT) was identified as one of the most potent inhibitors of human immunodeficiency virus (HIV) replication. However, FLT also showed severe toxicity so that it was abundant as a potential chemotherapeutic agent. Here, we describe various triphosphate prodrugs of FLT aiming for (a) a bypass of all phosphorylation steps needed to convert the nucleoside analogue into its triphosphate (TP) form, (b) an intracellular delivery of hydrolytically and enzymatically stable triphosphate derivatives, and (c) increasing the selectivity for HIV-RT vs three cellular DNA polymerases including the mitochondrial DNA polymerase γ. γ-Alkylated FLTTP compounds fulfill all of these requirements because these compounds proved highly resistant to dephosphorylation and showed strong selectivity for HIV-RT. Moreover, a prodrug form of these compounds proved to be nontoxic in CEM cells.
3'-氟-3'-脱氧胸苷（FLT）被鉴定为最有效的人类免疫缺陷病毒（HIV）复制抑制剂之一。然而，FLT 也表现出严重的毒性，因此它作为一种潜在的化疗药物而被广泛应用。在这里，我们描述了 FLT 的各种三磷酸前药，旨在（a）绕过将核苷类似物转化为三磷酸（TP）形式所需的所有磷酸化步骤，（b）将水解和酶稳定的三磷酸衍生物递送至细胞内，以及（c）提高对 HIV-RT 的选择性，而不是对包括线粒体 DNA 聚合酶 γ 在内的三种细胞 DNA 聚合酶的选择性。γ-烷基化 FLTTP 化合物满足所有这些要求，因为这些化合物被证明对去磷酸化具有高度抗性，并对 HIV-RT 表现出很强的选择性。此外，这些化合物的前药形式在 CEM 细胞中被证明是无毒的。
