Development of a novel class of glucose transporter inhibitors

摘要

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)γ agonist, was, in part, attributable to its ability to block glucose uptake independently of PPARγ, we used its PPARγ-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 (IC _(50), 2.5 μM), while not cytotoxic to prostate and mammary epithelial cells. This glucose uptake inhibition was associated with the inhibition of GLUT1 (IC _(50), 2 μM). 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.