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

Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, USA.
Bioorganic & medicinal chemistry letters (Impact Factor: 2.33). 04/2008; 18(6):2206-10. DOI: 10.1016/j.bmcl.2007.11.101
Source: PubMed

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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