10-Formyl-5,8,10-trideazafolic acid (10-formyl-TDAF): A potent inhibitor of glycinamide ribonucleotide transformylase

Dale L. Boger, Nancy Ellen Haynes, Paul A. Kitos, Mark S. Warren, Joseph Ramcharan, Ariane E. Marolewski, Stephen Benkovic

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Abstract

The synthesis of 10-formyl-5,8,10-trideazafolic acid (3) as a potential inhibitor of glycinamide ribonucleotide transformylase (GAR Tfase) is reported. The target compound was prepared by a convergent synthesis utilizing the alkylation of hydrazone 5 with benzylic bromide 6 to construct the core heterocycle 7. The aldehyde 3 and related agents were evaluated as inhibitors of purN GAR Tfase and avian AICAR Tfase. Compound 3 exhibited potent inhibition of GAR Tfase with a K(i) of 0.26 ± 0.05 μM. In contrast, 3 exhibited more moderate inhibition of aminoimidazole carboxamide ribonucleotide transformylase (AICAR Tfase), with K(i) of 7.6 ± 1.5 μM.

Original languageEnglish (US)
Pages (from-to)1817-1830
Number of pages14
JournalBioorganic and Medicinal Chemistry
Volume5
Issue number9
DOIs
Publication statusPublished - Sep 1 1997

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All Science Journal Classification (ASJC) codes

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

Cite this

Boger, D. L., Haynes, N. E., Kitos, P. A., Warren, M. S., Ramcharan, J., Marolewski, A. E., & Benkovic, S. (1997). 10-Formyl-5,8,10-trideazafolic acid (10-formyl-TDAF): A potent inhibitor of glycinamide ribonucleotide transformylase. Bioorganic and Medicinal Chemistry, 5(9), 1817-1830. https://doi.org/10.1016/S0968-0896(97)00120-X