Activation of p16 gene silenced by DNA methylation in cancer cells by phosphoramidate derivatives of 2'-deoxyzebularine.
Activation of p16 gene silenced by DNA methylation in cancer cells by phosphoramidate derivatives of 2'-deoxyzebularine.
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2-deoxyzebularine 的氨基磷酸酯衍生物可通过癌细胞中 DNA 甲基化来沉默 p16 基因的激活。
DOI：
10.1021/jm8005965
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发表时间：
2008
影响因子：
7.3
通讯作者：
Marquez,VictorE
中科院分区：
文献类型：
--
作者：
Yoo,ChristineB;Valente,Rocco;Congiatu,Costantino;Gavazza,Federica;Angel,Annette;Siddiqui,MaqboolA;Jones,PeterA;McGuigan,Christopher;Marquez,VictorE
We report herein the application of the phosphoramidate ProTide technology to improve the metabolism of the DNA methytransferase inhibitor, zebularine (Z). Zebularine is a riboside that must undergo a complex metabolic transformation before reaching the critical 2′-deoxyzebularine 5′-triphosphate (dZTP). Because 2′-deoxyzebularine (dZ) is not phosphorylated and therefore inactive, the ProTide strategy was employed to bypass the lack of phosphorylation of dZ and the inefficient reduction of zebularine 5′-diphosphate by ribonucleotide-diphosphate reductase required for zebularine. Several compounds were identified as more potent inhibitors of DNA methylation and stronger inducers ofp16tumor suppressor gene than zebularine. However, their activity was dependent on the administration of thymidine to overcome the potent inhibition of thymidylate synthase (TS) and deoxycytidine monophosphate (dCMP) deaminase by dZMP, which deprives cells of essential levels of thymidine. Intriguingly, the activity of the ProTides was cell line-dependent, and activation ofp16was manifest only in Cf-Pac-1 pancreatic ductal adenocarcinoma cells.
