Eukaryotic translation initiation factor 4E (eIF4E) is overexpressed in many cancers deregulating translational control of the cell cycle. mRNA 5' cap analogs targeting eIF4E are small molecules with the potential to counteract elevated levels of eIF4E in cancer cells. However, the practical utility of typical cap analogs is limited because of their reduced cell membrane permeability. Transforming the active analogs into their pronucleotide derivatives is a promising approach to overcome this obstacle. 7-Benzylguanosine monophosphate (bn7GMP) is a cap analog that has been successfully transformed into a cell-penetrating pronucleotide by conjugation of the phosphate moiety with tryptamine. In this work, we explored whether a similar strategy is applicable to other cap analogs, particularly phosphate-modified 7-methylguanine nucleotides. We report the synthesis of six new tryptamine conjugates containing N7-methylguanosine mono- and diphosphate and their analogs modified with thiophosphate moiety. These new potential pronucleotides and the expected products of their activation were characterized by biophysical and biochemical methods to determine their affinity towards eIF4E, their ability to inhibit translation in vitro, their susceptibility to enzymatic degradation and their turnover in cell extract. The results suggest that compounds containing the thiophosphate moiety may act as pronucleotides that release low but sustainable concentrations of 7-methylguanosine 5'-phosphorothioate (m7GMPS), which is a translation inhibitor with in vitro potency higher than bn7GMP.

中文翻译：

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探索作为磷酸酯修饰的7-甲基鸟嘌呤核苷酸的前核苷酸的色胺结合物，其靶向帽依赖性翻译。

真核翻译起始因子4E（eIF4E）在许多调节细胞周期翻译控制的癌症中过表达。靶向eIF4E的mRNA 5'帽类似物是小分子，具有抵消癌细胞中eIF4E水平升高的潜力。然而，由于其降低的细胞膜通透性，典型的帽类似物的实用性受到限制。将活性类似物转化成其前核苷酸衍生物是克服这一障碍的一种有前途的方法。7-苄基鸟苷单磷酸酯（bn7GMP）是一种帽类似物，已通过将磷酸部分与色胺结合而成功转化为可穿透细胞的核苷酸。在这项工作中，我们探讨了类似的策略是否适用于其他cap类似物，特别是磷酸修饰的7-甲基鸟嘌呤核苷酸。我们报告了六个新的包含N7-甲基鸟苷一磷酸和二磷酸及其类似物用硫代磷酸酯部分修饰的新型色胺结合物的合成。这些新的潜在前核苷酸及其激活的预期产物通过生物物理和生化方法进行表征，以确定它们对eIF4E的亲和力，体外抑制翻译的能力，对酶促降解的敏感性以及细胞提取物中的更新。结果表明，含有硫代磷酸酯部分的化合物可能充当原核苷酸，释放出低浓度但可持续的7-甲基鸟苷5'-硫代磷酸酯（m7GMPS），这是一种翻译抑制剂，体外效能高于bn7GMP。