Design, synthesis and biological evaluation of 10-CF3CO-DDACTHF analogues and derivatives as inhibitors of GAR Tfase and the de novo purine biosynthetic pathway

Joel Desharnais, Inkyu Hwang, Yan Zhang, Ali Tavassoli, Justin Baboval, Stephen J. Benkovic, Ian A. Wilson, Dale L. Boger

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15 Scopus citations


The synthesis and evaluation of analogues and key derivatives of 10-CF 3CO-DDACTHF as inhibitors of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide transformylase (AICAR Tfase) are reported. Polyglutamate analogues of 1 were evaluated as inhibitors of Escherichia coli and recombinant human (rh) GAR Tfase, and AICAR Tfase. Although the pentaglutamate 6 was found to be the most active inhibitor of the series tested against rhGAR Tfase (Ki=0.004 μM), little distinction between the mono-pentaglutamate derivatives was observed (K i=0.02-0.004 μM), suggesting that the principal role of the required polyglutamation of 1 is intracellular retention. In contrast, 1 and its defined polyglutamates 3-6 were much less inactive when tested against rhAICAR Tfase (Ki=65-0.120 μM) and very selective (≥100-fold) for rh versus E. coli GAR Tfase. Additional key analogues of 1 were examined (7 and 8) and found to be much less active (1000-fold) highlighting the exceptional characteristics of 1.

Original languageEnglish (US)
Pages (from-to)4511-4521
Number of pages11
JournalBioorganic and Medicinal Chemistry
Issue number20
StatePublished - Oct 1 2003

All Science Journal Classification (ASJC) codes

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

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