Synthesis of thiazole-4-carboxamide adenine dinucleotide. A powerful inhibitor of IMP dehydrogenase

Gulilat Gebeyehu, Victor E. Marquez, James A. Kelley, David A. Cooney, Hiremagalur N. Jayaram, David G. Johns

Research output: Contribution to journalArticle

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Abstract

The chemical synthesis of thiazole-4-carboxamide adenine dinucleotide (TAD), previously identified as the active anabolite of the oncolytic 2-β-D-ribofuranosylthiazole-4-carboxamide (TR), has been achieved by three different approaches: (1) incubation of adenosine 5′-monophosphate (AMP) and 2-β-D-ribofuranosylthiazole-4-carboxamide 5′-monophosphate (TRMP) with excess DCC in aqueous pyridine, (2) reaction of adenosine 5′-phosphoromorpholidate with TRMP in pyridine, and (3) reaction of adenosine-5′-phosphoric di-n-butylphosphinothioic anhydride with TRMP in the presence of AgNO3. While the first approach produced only traces of TAD, the last two afforded 31 and 16% yields, respectively, of isolated TAD. The synthetic material was indistinguishable from biosynthesized TAD as judged by its HPLC behavior, NMR, UV and mass spectra, enzymatic resistance to alkaline phosphatase and susceptibility to venom phosphodiesterase, IMP dehydrogenase inhibitory activity, and cytotoxicity. TAD and TR were equally effective against murine P388 leukemia when employed at equimolar doses.

Original languageEnglish (US)
Pages (from-to)922-925
Number of pages4
JournalJournal of Medicinal Chemistry
Volume26
Issue number6
StatePublished - 1983
Externally publishedYes

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IMP Dehydrogenase
tiazofurin
Adenosine
Leukemia P388
Anhydrides
Venoms
Phosphoric Diester Hydrolases
Adenosine Monophosphate
Cytotoxicity
Alkaline Phosphatase
High Pressure Liquid Chromatography
Nuclear magnetic resonance
thiazole-4-carboxamide adenine dinucleotide

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Gebeyehu, G., Marquez, V. E., Kelley, J. A., Cooney, D. A., Jayaram, H. N., & Johns, D. G. (1983). Synthesis of thiazole-4-carboxamide adenine dinucleotide. A powerful inhibitor of IMP dehydrogenase. Journal of Medicinal Chemistry, 26(6), 922-925.

Synthesis of thiazole-4-carboxamide adenine dinucleotide. A powerful inhibitor of IMP dehydrogenase. / Gebeyehu, Gulilat; Marquez, Victor E.; Kelley, James A.; Cooney, David A.; Jayaram, Hiremagalur N.; Johns, David G.

In: Journal of Medicinal Chemistry, Vol. 26, No. 6, 1983, p. 922-925.

Research output: Contribution to journalArticle

Gebeyehu, G, Marquez, VE, Kelley, JA, Cooney, DA, Jayaram, HN & Johns, DG 1983, 'Synthesis of thiazole-4-carboxamide adenine dinucleotide. A powerful inhibitor of IMP dehydrogenase', Journal of Medicinal Chemistry, vol. 26, no. 6, pp. 922-925.
Gebeyehu G, Marquez VE, Kelley JA, Cooney DA, Jayaram HN, Johns DG. Synthesis of thiazole-4-carboxamide adenine dinucleotide. A powerful inhibitor of IMP dehydrogenase. Journal of Medicinal Chemistry. 1983;26(6):922-925.
Gebeyehu, Gulilat ; Marquez, Victor E. ; Kelley, James A. ; Cooney, David A. ; Jayaram, Hiremagalur N. ; Johns, David G. / Synthesis of thiazole-4-carboxamide adenine dinucleotide. A powerful inhibitor of IMP dehydrogenase. In: Journal of Medicinal Chemistry. 1983 ; Vol. 26, No. 6. pp. 922-925.
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