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Synthesis and biological evaluation of N-{4- 5-(2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-2-(2,2,2-trifluoro acetyl)pentyl)benzoyl}-L-glutamic acid as a potential inhibitor of GAR Tfase and the de novo purine biosynthetic pathway

Academic Article
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Overview

related to degree

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

authors

  • Cheng, H.
  • Hwang, I.
  • Chong, Y. H.
  • Tavassoli, A.
  • Webb, M. E.
  • Zhang, Yan Jessie
  • Wilson, Ian
  • Benkovic, S. J.
  • Boger, Dale

publication date

  • May 2005

journal

  • Bioorganic & Medicinal Chemistry  Journal

abstract

  • The synthesis and evaluation of N-[4-[5-(2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl]-L-glutamic acid (2) as an inhibitor of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide ribonucleotide transformylase (AICAR Tfase) are reported. The inhibitor 2 was prepared in a convergent synthesis involving C-alkylation of methyl 4-(4,4,4-trifluoro-3-dimethylhydrazonobutyl)benzoate with 1-chloro-3-iodopropane followed by construction of the pyrimidinone ring. Compound 2 was found to be an effective inhibitor of recombinant human GAR Tfase (K(i) = 0.50 microM), whereas it was inactive (K(i) > 100 microM) against E. coli GAR Tfase as well as recombinant human AICAR Tfase. Compound 2 exhibited modest, purine-sensitive growth inhibitory activity against the CCRF-CEM cell line (IC50 = 6.0 microM).

subject areas

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Glutamic Acid
  • Humans
  • Hydroxymethyl and Formyl Transferases
  • Molecular Structure
  • Phosphoribosylaminoimidazolecarboxamide Formyltransferase
  • Phosphoribosylglycinamide Formyltransferase
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Purines
  • Pyrimidines
  • Structure-Activity Relationship
  • Tumor Cells, Cultured
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Identity

International Standard Serial Number (ISSN)

  • 0968-0896

Digital Object Identifier (DOI)

  • 10.1016/j.bme.2004.11.049

PubMed ID

  • 15848772
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Additional Document Info

start page

  • 3593

end page

  • 3599

volume

  • 13

issue

  • 10

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