Prodrug thiamine analogs as inhibitors of the enzyme transketolase

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• 作者：Yvan Le Huerou ; Indrani Gunawardana ; Allen A. Thomas ; Steven A. Boyd ; Jason de Meese ; Walter deWolf ; Steven S. Gonzales ; May Han ; Laura Hayter ; Tomas Kaplan ; Christine Lemieux ; Patrice Lee ; Jed Pheneg
• 关键词：Thiamine ; Prodrug ; Transketolase ; Disulfides ; Pharmacokinetic ; Thiocarbonate
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2008
• 出版时间：15 January 2008
• 年：2008
• 卷：18
• 期：2
• 页码：505-508
• 全文大小：262 K

文摘

Transketolase, a key enzyme in the pentose phosphate pathway, has been suggested as a target for inhibition in the treatment of cancer. Compound 5a (‘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 the transketolase cofactor thiamine, is a potent transketolase inhibitor but suffers from poor pharmacokinetics due to high clearance and C_max linked toxicity. An efficient way of improving the pharmacokinetic profile of 5a is to prepare oxidized prodrugs which are slowly reduced in vivo yielding longer, sustained blood levels of the drug. The synthesis of such prodrugs and their evaluation in rodent models is reported.