Synthesis, in vitro and in vivo activity of thiamine antagonist transketolase inhibitors

Allen A. Thomas, Y. Le Huerou, J. De Meese, Indrani Gunawardana, Tomas Kaplan, Todd T. Romoff, Stephen S. Gonzales, Kevin Condroski, Steven A. Boyd, Josh Ballard, Bryan Bernat, Walter DeWolf, May Han, Patrice Lee, Christine Lemieux, Robin Pedersen, Jed Pheneger, Greg Poch, Darin Smith, Francis SullivanSolly Weiler, S. Kirk Wright, Jie Lin, Barb Brandhuber, Guy Vigers

Research output: Contribution to journalArticlepeer-review

39 Scopus citations


Tumor cells extensively utilize the pentose phosphate pathway for the synthesis of ribose. Transketolase is a key enzyme in this pathway and has been suggested as a target for inhibition in the treatment of cancer. In a pharmacodynamic study, nude mice with xenografted HCT-116 tumors were dosed with 1 ('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 thiamine, the co-factor of transketolase. Transketolase activity was almost completely suppressed in blood, spleen, and tumor cells, but there was little effect on the activity of the other thiamine-utilizing enzymes α-ketoglutarate dehydrogenase or glucose-6-phosphate dehydrogenase. Synthesis and SAR of transketolase inhibitors is described.

Original languageEnglish (US)
Pages (from-to)2206-2210
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Issue number6
StatePublished - Mar 15 2008
Externally publishedYes


  • Cancer
  • Metabolism
  • Pyrophosphate
  • Thiamine
  • Transketolase

ASJC Scopus subject areas

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


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