Synthesis and biological evaluation of N-{4-[5-(2,4-diamino-6-oxo-1,6- dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl}-L-glutamic acid as a potential inhibitor of GAR Tfase and the de novo purine biosynthetic pathway

Heng Cheng, Inkyu Hwang, Youhoon Chong, Ali Tavassoli, Michael E. Webb, Yan Zhang, Ian A. Wilson, Stephen J. Benkovic, Dale L. Boger

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Abstract

The synthesis and evaluation of N-{4-[5-(2,4-diamino-6-oxo-1,6- dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl}-l-glutamic acid (2) as an inhibitor of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide ribonucleotide transformylase (AICAR Tfase) are reported. The inhibitor 2 was prepared in a convergent synthesis involving C-alkylation of methyl 4-(4,4,4-trifluoro-3-dimethylhydrazonobutyl)benzoate with 1-chloro-3-iodopropane followed by construction of the pyrimidinone ring. Compound 2 was found to be an effective inhibitor of recombinant human GAR Tfase (Ki = 0.50 μM), whereas it was inactive (Ki > 100 μM) against E. coli GAR Tfase as well as recombinant human AICAR Tfase. Compound 2 exhibited modest, purine-sensitive growth inhibitory activity against the CCRF-CEM cell line (IC50 = 6.0 μM).

Original languageEnglish (US)
Pages (from-to)3593-3599
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume13
Issue number10
DOIs
StatePublished - May 15 2005

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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