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. 2008 Mar 15;18(6):2206-10.
doi: 10.1016/j.bmcl.2007.11.101. Epub 2007 Dec 3.

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

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

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

Allen A Thomas et al. Bioorg Med Chem Lett. .

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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