Thomas Allen A, Le Huerou Y, De Meese J, 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
Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, USA.
Bioorg Med Chem Lett. 2008 Mar 15;18(6):2206-10. doi: 10.1016/j.bmcl.2007.11.101. Epub 2007 Dec 3.
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.
肿瘤细胞广泛利用磷酸戊糖途径来合成核糖。转酮醇酶是该途径中的关键酶，并且已被提议作为癌症治疗中的抑制靶点。在一项药效学研究中，给移植了HCT - 116肿瘤的裸鼠注射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 - 鎓氯化物盐酸盐），它是硫胺（转酮醇酶的辅酶）的类似物。转酮醇酶活性在血液、脾脏和肿瘤细胞中几乎被完全抑制，但对其他利用硫胺的酶α - 酮戊二酸脱氢酶或葡萄糖 - 6 - 磷酸脱氢酶的活性影响很小。文中描述了转酮醇酶抑制剂的合成及构效关系。
