Non-charged thiamine analogs as inhibitors of enzyme transketolase

Allen A. Thomas, J. De Meese, Y. Le Huerou, Steven A. Boyd, Todd T. Romoff, Steven S. Gonzales, Indrani Gunawardana, Tomas Kaplan, Francis Sullivan, Kevin Condroski, Joseph P. Lyssikatos, Thomas D. Aicher, Josh Ballard, Bryan Bernat, Walter DeWolf, May Han, Christine Lemieux, Darin Smith, Solly Weiler, S. Kirk WrightGuy Vigers, Barb Brandhuber

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Inhibition of the thiamine-utilizing enzyme transketolase (TK) has been linked with diminished tumor cell proliferation. Most thiamine antagonists have a permanent positive charge on the B-ring, and it has been suggested that this charge is required for diphosphorylation by thiamine pyrophosphokinase (TPPK) and binding to TK. We sought to make neutral thiazolium replacements that would be substrates for TPPK, while not necessarily needing thiamine transporters (ThTr1 and ThTr2) for cell penetration. The synthesis, SAR, and structure-based rationale for highly potent non-thiazolium TK antagonists are presented.

Original languageEnglish (US)
Pages (from-to)509-512
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume18
Issue number2
DOIs
StatePublished - Jan 15 2008

Keywords

  • Deazathiamine
  • Pyrazolothiamine
  • Pyrophosphate
  • Pyrophosphokinase
  • Thiamine
  • Thiazolone
  • Transketolase

ASJC Scopus subject areas

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

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  • Cite this

    Thomas, A. A., De Meese, J., Le Huerou, Y., Boyd, S. A., Romoff, T. T., Gonzales, S. S., Gunawardana, I., Kaplan, T., Sullivan, F., Condroski, K., Lyssikatos, J. P., Aicher, T. D., Ballard, J., Bernat, B., DeWolf, W., Han, M., Lemieux, C., Smith, D., Weiler, S., ... Brandhuber, B. (2008). Non-charged thiamine analogs as inhibitors of enzyme transketolase. Bioorganic and Medicinal Chemistry Letters, 18(2), 509-512. https://doi.org/10.1016/j.bmcl.2007.11.098