2ʹ-O-Acyl-6-thioinosine Cyclic 3ʹ,5ʹ-Phosphates as Prodrugs of Thioinosinic Acid

Rich B. Meyer, Thomas E. Stone, Buddy Ullman

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

A series of 2ʹ-O-acyl derivatives of 6-thioinosine cyclic 3ʹ,5ʹ-phosphate (6-HS-cRMP) were prepared and examined for their cytotoxic effects on S49 mouse lymphoma cells which were deficient in hypoxanthine-guanine phosphoribosyltransferase (HGPRTase). Cytotoxicity increased with the lipophilicity of the acyl group to a lowest EC50 of 65 µM for the 2ʹ-O-palmityl derivative. Addition of a mutation in the gene for cAMP-dependent protein kinase to the HGPRTase-deficient cell line confers resistance to 2ʹ-0-butyryl-cAMP but not to 2ʹ-O-butyryl-6-HS-cRMP, indicating that the latter does not exert its toxic effect via activation of protein kinase. The time course of cell kill by 2ʹ-O-palmityl-6-HS-cRMP resembled that of 6-mercaptopurine and not that of cyclic AMP in these cells. The data suggest that the intact cyclic nucleotides are penetrating the cells and being converted, by phosphodiesterase action and deacylation, to the first toxic metabolite of 6-mercaptopurine, thioinosinic acid.

Original languageEnglish (US)
Pages (from-to)811-815
Number of pages5
JournalJournal of Medicinal Chemistry
Volume22
Issue number7
DOIs
StatePublished - Feb 1 1979

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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