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

  • Bioorg Med Chem Lett. 2008 Mar 15;18(6):2206-10. doi: 10.1016/j.bmcl.2007.11.101.
Allen A Thomas  1 ,  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 Sullivan ,  Solly Weiler ,  S Kirk Wright ,  Jie Lin ,  Barb Brandhuber ,  Guy Vigers
Affiliations
PMID: 18267359 DOI: 10.1016/j.bmcl.2007.11.101
Abstract

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 alpha-ketoglutarate dehydrogenase or glucose-6-phosphate dehydrogenase. Synthesis and SAR of Transketolase inhibitors is described.

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