Design, synthesis, and biological evaluation of 10-methanesulfonyl-DDACTHF, 10-methanesulfonyl-5-DACTHF, and 10-methylthio-DDACTHF as potent inhibitors of GAR Tfase and the de novo purine biosynthetic pathway

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

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4 Scopus citations

Abstract

The synthesis and evaluation of 10-methanesulfonyl-DDACTHF (1), 10-methanesulfonyl-5-DACTHF (2), and 10-methylthio-DDACTHF (3) as potential inhibitors of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide ribonucleotide transformylase (AICAR Tfase) are reported. The compounds 10-methanesulfonyl-DDACTHF (1, Ki = 0.23 μM), 10-methanesulfonyl-5-DACTHF (2, Ki = 0.58 μM), and 10-methylthio-DDACTHF (3, Ki = 0.25 μM) were found to be selective and potent inhibitors of recombinant human GAR Tfase. Of these, 3 exhibited exceptionally potent, purine sensitive growth inhibition activity (3, IC 50 = 100 nM) against the CCRF-CEM cell line being 3-fold more potent than Lometrexol and 30-fold more potent than the parent, unsubstituted DDACTHF, whereas 1 and 2 exhibited more modest growth inhibition activity (1, IC 50 = 1.0 μM and 2, IC50 = 2.0 μM).

Original languageEnglish (US)
Pages (from-to)3577-3585
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume13
Issue number10
DOIs
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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