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

39 Scopus citations

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-/3-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
DOIs
StatePublished - Jun 1983

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    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. https://doi.org/10.1021/jm00360a025