Development of a Novel Class of Glucose Transporter Inhibitors

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• 作者：Dasheng Wang ; Po-Chen Chu ; Chia-Ning Yang ; Ribai Yan ; Yu-Chung Chuang ; Samuel K. Kulp ; Ching-Shih Chen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：April 26, 2012
• 年：2012
• 卷：55
• 期：8
• 页码：3827-3836
• 全文大小：442K
• 年卷期：v.55,no.8(April 26, 2012)
• ISSN：1520-4804

文摘

On the basis of our finding that the antitumor effect of 5-{4-[(1-methylcyclohexyl)methoxy]benzyl}thiazolidine-2,4-dione, a thiazolidinedione peroxisome proliferator-activated receptor (PPAR)纬 agonist, was, in part, attributable to its ability to block glucose uptake independently of PPAR纬, we used its PPAR纬-inactive analogue to develop a novel class of glucose transporter (GLUT) inhibitors. This lead optimization led to compound 30 {5-(4-hydroxy-3-trifluoromethylbenzylidene)-3-[4,4,4-trifluoro-2-methyl-2-(2,2,2-trifluoroethyl)butyl]thiazolidine-2,4-dione} as the optimal agent, which exhibited high antitumor potency through the suppression of glucose uptake (IC₅₀, 2.5 渭M), while not cytotoxic to prostate and mammary epithelial cells. This glucose uptake inhibition was associated with the inhibition of GLUT1 (IC₅₀, 2 渭M). Moreover, the mechanism of antitumor action of compound 30 was validated by its effect on a series of energy restriction-associated cellular responses. Homology modeling analysis suggests that the inhibitory effect of compound 30 on glucose entry was attributable to its ability to bind to the GLUT1 channel at a site distinct from that of glucose.