2′-O-acyl-6-thioinosine cyclic 3′,5′-phosphates as prodrugs of thioinosinic acid

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

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

A series of 2′-O-acyl derivatives of 6-thioinosine cyclic 3′,5′-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 2′-O-palmityl derivative. Addition of a mutation in the gene for cAMP-dependent protein kinase to the HGPRTase-deficient cell line confers resistance to 2′-O-butyryl-cAMP but not to 2′-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 2′-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
StatePublished - 1979

Fingerprint

HS 6
Thioinosine
Prodrugs
Hypoxanthine Phosphoribosyltransferase
6-Mercaptopurine
Poisons
Phosphates
Derivatives
Cyclic Nucleotides
Phosphoric Diester Hydrolases
Cytotoxicity
Metabolites
Cyclic AMP-Dependent Protein Kinases
Cyclic AMP
Protein Kinases
Genes
Chemical activation
Cells
Lymphoma
Cell Line

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

2′-O-acyl-6-thioinosine cyclic 3′,5′-phosphates as prodrugs of thioinosinic acid. / Meyer, Rich B.; Stone, Thomas E.; Ullman, Buddy.

In: Journal of Medicinal Chemistry, Vol. 22, No. 7, 1979, p. 811-815.

Research output: Contribution to journalArticle

Meyer, Rich B. ; Stone, Thomas E. ; Ullman, Buddy. / 2′-O-acyl-6-thioinosine cyclic 3′,5′-phosphates as prodrugs of thioinosinic acid. In: Journal of Medicinal Chemistry. 1979 ; Vol. 22, No. 7. pp. 811-815.
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