- Synthesis, in vitro and in vivo activity of thiamine antagonist transketolase inhibitors
-
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.
- Thomas, Allen A.,Le Huerou,De Meese,Gunawardana, Indrani,Kaplan, Tomas,Romoff, Todd T.,Gonzales, Stephen S.,Condroski, Kevin,Boyd, Steven A.,Ballard, Josh,Bernat, Bryan,DeWolf, Walter,Han, May,Lee, Patrice,Lemieux, Christine,Pedersen, Robin,Pheneger, Jed,Poch, Greg,Smith, Darin,Sullivan, Francis,Weiler, Solly,Wright, S. Kirk,Lin, Jie,Brandhuber, Barb,Vigers, Guy
-
p. 2206 - 2210
(2008/12/20)
-
- THIOALKENEAMIDES AS TRANSKETOLASE INHIBITORS
-
The present invention provides thioalkeneamides of formula (I) which are useful as transketolase inhibitors: wherein R1, R2, R3, R4, R5, R6, Ra-Rd, n and ring A are as defined herein. The present invention also provides pharmaceutical compositions comprising the compounds of formula (I). The invention provides methods for inhibiting transketolase activity, reducing cellular ribose-5-phosphate levels, inhibiting nucleic acid synthesis, inhibiting cell proliferation and tumor cell growth in vitro and in vivo, stimulating apoptosis in tumor cells and treating cancer by administering a compound of formula (I) or a pharmaceutical composition thereof.
- -
-
Page/Page column 37
(2008/06/13)
-
