Faculty of Chemistry, University of Warsaw, 1 Pasteur St., 02-093, Warsaw, Poland.
Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, 02-089, Warsaw, Poland.
ChemMedChem. 2023 Feb 14;18(4):e202200490. doi: 10.1002/cmdc.202200490. Epub 2023 Jan 19.
Aryloxy triester phosphoramidate methodology, commonly known as ProTide technology, is one of the most widely used prodrug approaches applied to therapeutic nucleosides. This approach has been used extensively by the pharmaceutical industry and researchers in medicinal chemistry. Herein we report our adaptation of this effective method for the synthesis of bioactive 5'-mRNA cap analogues as inhibitors for targeting cap-dependent translation. The synthesis was performed in two main stages: preparation of N2-modified guanosine analogues and their subsequent transformation into prodrugs using phenylethoxy-l-alaninyl phosphorochloridate. The prepared pro-nucleotide cap analogues were tested for their capacity in enzymatic activation, inhibitory properties in a rabbit reticulocyte lysate system, and passive membrane translocation properties.
芳氧基三酯磷酰胺方法，通常称为 ProTide 技术，是应用于治疗性核苷的最广泛使用的前药方法之一。该方法已被制药行业和药物化学研究人员广泛使用。在此，我们报告了我们对这种有效方法的适应，用于合成作为针对帽依赖性翻译的靶标的生物活性 5'-mRNA 帽类似物。合成分两个主要阶段进行：制备 N2-修饰的鸟苷类似物及其随后使用苯乙氧基-l-丙氨酰基磷酰氯转化为前药。测试了制备的前核苷酸帽类似物在酶激活中的能力、在兔网织红细胞裂解物系统中的抑制特性以及被动膜转位特性。
