Synthesis, in vitro and in vivo activity of thiamine antagonist transketolase inhibitors
Synthesis, in vitro and in vivo activity of thiamine antagonist transketolase inhibitors
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DOI：
10.1016/j.bmcl.2007.11.101
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发表时间：
2008-03-15
影响因子：
2.7
通讯作者：
Vigers, Guy
中科院分区：
文献类型：
--
作者：
Thomas, Allen A.;Le Huerou, Y.;Vigers, Guy
肿瘤细胞广泛利用戊糖磷酸途径合成核糖。转酮醇酶是该途径中的关键酶，并且已被建议作为癌症治疗中的抑制靶标。在药效学研究中，向具有异种移植HCT-116肿瘤的裸鼠给药1（“N3”-吡啶基硫胺“; 3-（6-甲基-2-氨基-吡啶-3-基甲基）-5-（2-羟乙基）-4-甲基-噻唑-3-鎓盐酸盐），一种硫胺素类似物，转酮醇酶的辅因子。在血液、脾脏和肿瘤细胞中，转酮醇酶活性几乎完全被抑制，但对其他硫胺素利用酶α-酮戊二酸脱氢酶或葡萄糖-6-磷酸脱氢酶的活性几乎没有影响。介绍了转酮醇酶抑制剂的合成及构效关系。(C)2007爱思唯尔有限公司保留所有权利。
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-hydroxyethyl)-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. (C) 2007 Elsevier Ltd. All rights reserved.