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Activation of p16 Gene Silenced by DNA Methylation in Cancer Cells by Phosphoramidate Derivatives of 2 '-Deoxyzebularine

  1. Author:
    Yoo, C. B.
    Valente, R.
    Congiatu, C.
    Gavazza, F.
    Angel, A.
    Siddiqui, M. A.
    Jones, P. A.
    McGuigan, C.
    Marquez, V. E.

  2. Author Address

    Yoo, Christine B.; Jones, Peter A.] Univ So Calif, Dept Biochem, Keck Sch Med, USC Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Yoo, Christine B.; Jones, Peter A.] Univ So Calif, Dept Mol Biol, Keck Sch Med, USC Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Valente, Rocco, Congiatu, Costantino, Gavazza, Federica, Angel, Annette, McGuigan, Christopher] Cardiff Univ, Welsh Sch Pharm, Cardiff CF10 3XF, S Glam, Wales. [Siddiqui, Maqbool A.; Marquez, Victor E.] NIH, Natl Canc Inst, Ctr Canc Res, Med Chem Lab, Frederick, MD 21702 USA.
    1. Year: 2008
  2. Journal: Journal of Medicinal Chemistry
    1. 51
    2. 23
    3. Pages: 7593-7601
  4. Type of Article: Article
  1. Abstract:

    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 of p16 tumor 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 of p16 was manifest only in Cf-Pac-1 pancreatic ductal adenocarcinoma. cells.

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External Sources

  1. PMID: 19006382

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