Aryloxy phosphoroamidate triesters, known as ProTides, are a class of prodrugs developed to enhance the physicochemical and pharmacological properties of therapeutic nucleosides. This approach has been extensively investigated in the antiviral and anticancer areas leading to three prodrugs on the market and several others in clinical stage. In this article we have prepared the PS analogues of three ProTides that have reached the clinic as anticancer agents. These novel PS ProTides were tested for their capacity in enzymatic activation and for their cytotoxic properties against a panel of solid and liquid tumor cell lines. As expected, the replacement of the PO with a PS bond led to increased metabolic stability albeit concomitant to a decrease in potency. Surprisingly, the intermediate formed after the first activation step of a thiophosphoramidate with carboxypeptidase Y is not the expected PS aminoacyl product but the corresponding PO aminoacyl compound.

中文翻译：

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抗癌核苷类似物芳氧基硫代磷酸酰胺三酯的设计、合成及生物学评价

芳氧基氨基磷酸酯三酯，称为 ProTides，是一类为增强治疗性核苷的物理化学和药理学特性而开发的前药。这种方法已在抗病毒和抗癌领域进行了广泛的研究，导致三种前药上市，其他几种药物处于临床阶段。在本文中，我们制备了三种 ProTides 的 PS 类似物，它们已作为抗癌药物进入临床。测试了这些新型 PS ProTides 的酶激活能力以及针对一组固体和液体肿瘤细胞系的细胞毒性特性。正如预期的那样，用 PS 键取代 PO 会导致代谢稳定性增加，尽管同时会导致效力下降。令人惊讶的是，硫代磷酸酰胺酯与羧肽酶Y的第一个活化步骤后形成的中间体不是预期的PS氨酰产物，而是相应的PO氨酰化合物。