Synthesis and biological evaluation of α- and γ-carboxamide derivatives of 10-CF3CO-DDACTHF

Youhoon Chong, Inkyu Hwang, Ali Tavassoli, Yan Zhang, Ian A. Wilson, Stephen J. Benkovic, Dale L. Boger

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7 Scopus citations


Structurally-related, but non-polyglutamylatable, derivatives of 10-CF 3CO-DDACTHF (1), which incorporate l-glutamine (2) and l-isoglutamine (3) in place of l-glutamate, were prepared and evaluated as inhibitors of recombinant human (rh) GAR Tfase. While the l-glutamate α-carboxamide derivative 3 was much less effective as a rhGAR Tfase inhibitor (Ki = 4.8 μM) and inactive in cellular functional assays, the γ-carboxamide derivative 2 was found to be a potent and selective rhGAR Tfase inhibitor (Ki = 0.056 μM) being only 4-fold less potent than 1 (K i = 0.015 μM). Moreover, 2 was effective in cellular functional assays exhibiting purine sensitive cytotoxic activity (IC50 = 300 nM, CCRF-CEM) only 20-fold less potent than 1 (IC50 = 16 nM), consistent with inhibition of de novo purine biosynthesis via selective inhibition of GAR Tfase. Like 1, 2 is transported into the cell by the reduced folate carrier. Unlike 1, the functional activity of 2 is not dependent upon FPGS polyglutamylation.

Original languageEnglish (US)
Pages (from-to)3587-3592
Number of pages6
JournalBioorganic and Medicinal Chemistry
Issue number10
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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