Functionalized analogues of 5,8,10-trideazafolate: Development of an enzyme-assembled tight binding inhibitor of GAR Tfase and a potential irreversible inhibitor of AICAR Tfase

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

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

A set of inhibitors 3 and 4 of GAR and AICAR Tfase based on the TDAF core which contain an sp2 C-10 carbon atom replacing N-10 of the natural cofactor are detailed. Both possess electrophilic olefins and the potential of trapping the reacting amine of the substrates GAR and AICAR by a Michael addition at the enzyme active site to provide an enzyme-assembled tight binding inhibitor. While these agents did not display such characteristics and served as simple competitive inhibitors of GAR Tfase and AICAR Tfase, inhibitor 15 prepared in the conversion of 3 to 4 may provide an enzyme-assembled tight binding inhibitor of GAR Tfase upon reaction with the substrate GAR and may inactivate AICAR Tfase by virtue of alkylation of an active site residue.

Original languageEnglish (US)
Pages (from-to)1839-1846
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume5
Issue number9
DOIs
StatePublished - Sep 1 1997

All Science Journal Classification (ASJC) codes

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

Fingerprint Dive into the research topics of 'Functionalized analogues of 5,8,10-trideazafolate: Development of an enzyme-assembled tight binding inhibitor of GAR Tfase and a potential irreversible inhibitor of AICAR Tfase'. Together they form a unique fingerprint.

  • Cite this