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

Academic Article
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Overview

related to degree

  • Zhang, Yan Jessie, Ph.D. in Biology, Scripps Research 2001 - 2004

authors

  • Chong, Y.
  • Hwang, I.
  • Tavassoli, A.
  • Zhang, Yan Jessie
  • Wilson, Ian
  • Benkovic, S. J.
  • Boger, Dale

publication date

  • May 2005

journal

  • Bioorganic & Medicinal Chemistry  Journal

abstract

  • Structurally-related, but non-polyglutamylatable, derivatives of 10-CF3CO-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 alpha-carboxamide derivative 3 was much less effective as a rhGAR Tfase inhibitor (K(i) = 4.8 microM) and inactive in cellular functional assays, the gamma-carboxamide derivative 2 was found to be a potent and selective rhGAR Tfase inhibitor (K(i) = 0.056 microM) being only 4-fold less potent than 1 (K(i) = 0.015 microM). 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.

subject areas

  • Amides
  • Antineoplastic Agents
  • Cell Proliferation
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors
  • Folic Acid Antagonists
  • Humans
  • Hydroxymethyl and Formyl Transferases
  • Inhibitory Concentration 50
  • Molecular Structure
  • Phosphoribosylaminoimidazolecarboxamide Formyltransferase
  • Phosphoribosylglycinamide Formyltransferase
  • Purines
  • Structure-Activity Relationship
  • Tetrahydrofolates
  • Tumor Cells, Cultured
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Identity

International Standard Serial Number (ISSN)

  • 0968-0896

Digital Object Identifier (DOI)

  • 10.1016/j.bme.2004.11.050

PubMed ID

  • 15848771
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Additional Document Info

start page

  • 3587

end page

  • 3592

volume

  • 13

issue

  • 10

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