Prodrug thiamine analogs as inhibitors of the enzyme transketolase

Yvan Le Huerou, Indrani Gunawardana, Allen A. Thomas, Steven A. Boyd, Jason de Meese, Walter deWolf, Steven S. Gonzales, May Han, Laura Hayter, Tomas Kaplan, Christine Lemieux, Patrice Lee, Jed Pheneger, Gregory Poch, Todd T. Romoff, Francis Sullivan, Solly Weiler, S. Kirk Wright, Jie Lin

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Transketolase, a key enzyme in the pentose phosphate pathway, has been suggested as a target for inhibition in the treatment of cancer. Compound 5a ('N3′-pyridyl thiamine'; 3-(6-methyl-2-amino-pyridin-3-ylmethyl)-5-(2-hydroxy-ethyl)-4-methyl-thiazol-3-ium chloride hydrochloride), an analog of the transketolase cofactor thiamine, is a potent transketolase inhibitor but suffers from poor pharmacokinetics due to high clearance and Cmax linked toxicity. An efficient way of improving the pharmacokinetic profile of 5a is to prepare oxidized prodrugs which are slowly reduced in vivo yielding longer, sustained blood levels of the drug. The synthesis of such prodrugs and their evaluation in rodent models is reported.

Original languageEnglish (US)
Pages (from-to)505-508
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume18
Issue number2
DOIs
Publication statusPublished - Jan 15 2008

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Keywords

  • Disulfides
  • Pharmacokinetic
  • Prodrug
  • Thiamine
  • Thiocarbonate
  • Transketolase

ASJC Scopus subject areas

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

Cite this

Le Huerou, Y., Gunawardana, I., Thomas, A. A., Boyd, S. A., de Meese, J., deWolf, W., ... Lin, J. (2008). Prodrug thiamine analogs as inhibitors of the enzyme transketolase. Bioorganic and Medicinal Chemistry Letters, 18(2), 505-508. https://doi.org/10.1016/j.bmcl.2007.11.100