3′-Deoxyadenosine (3′-dA, Cordycepin, 1) is a nucleoside analogue with anticancer properties, but its clinical development has been hampered due to its deactivation by adenosine deaminase (ADA) and poor cellular uptake due to low expression of the human equilibrative transporter (hENT1). Here, we describe the synthesis and characterization of NUC-7738 (7a), a 5′-aryloxy phosphoramidate prodrug of 3′-dA. We show in vitro evidence that 7a is an effective anticancer drug in a panel of solid and hematological cancer cell lines, showing its preferential cytotoxic effects on leukemic stem cells. We found that unlike 3′-dA, the activity of 7a was independent of hENT1 and kinase activity. Furthermore, it was resistant to ADA metabolic deactivation. Consistent with these findings, 7a showed increased levels of intracellular 3′-deoxyadenosine triphosphate (3′-dATP), the active metabolite. Mechanistically, levels of intracellular 3′-dATP were strongly associated with in vitro potency. NUC-7738 is now in Phase II, dose-escalation study in patients with advanced solid tumors.

中文翻译：

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NUC-7738（一种 3'-脱氧腺苷的芳氧基磷酰胺酯）的合成和表征，作为一种潜在的抗癌剂

3′-脱氧腺苷（3′-dA，虫草素，1）是一种具有抗癌特性的核苷类似物，但由于其被腺苷脱氨酶（ADA）失活以及由于人类低表达而导致细胞摄取不良，其临床开发受到阻碍。平衡转运蛋白（hENT1）。在这里，我们描述了 NUC-7738 ( 7a )（一种 3'-dA 的 5'-芳氧基氨基磷酸酯前药）的合成和表征。我们的体外证据表明， 7a在一组实体和血液癌细胞系中是一种有效的抗癌药物，显示出其对白血病干细胞的优先细胞毒性作用。我们发现，与 3'-dA 不同， 7a的活性独立于 hENT1 和激酶活性。此外，它还能抵抗 ADA 代谢失活。与这些发现一致，7a显示细胞内活性代谢物 3'-脱氧腺苷三磷酸 (3'-dATP) 水平增加。从机制上讲，细胞内 3'-dATP 水平与体外效力密切相关。NUC-7738 目前正处于晚期实体瘤患者的 II 期剂量递增研究中。