title: Development of a novel class of glucose transporter inhibitors.
abstract: 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.
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Dasheng
authors.initials: D
authors.lastname: Wang
authors.forename: Po-Chen
authors.initials: PC
authors.lastname: Chu
authors.forename: Chia-Ning
authors.initials: CN
authors.lastname: Yang
authors.forename: Ribai
authors.initials: R
authors.lastname: Yan
authors.forename: Yu-Chung
authors.initials: YC
authors.lastname: Chuang
authors.forename: Samuel K
authors.initials: SK
authors.lastname: Kulp
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D045744:Cell Line, Tumor; D051246:Glucose Transport Proteins, Facilitative / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D047495:PPAR gamma / Q000819:agonists; D045162:Thiazolidinediones / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: C573557:5-(4-hydroxy-3-trifluoromethylbenzylidene)-3-(4,4,4-trifluoro-2-methyl-2-(2,2,2-trifluoroethyl)butyl)thiazolidine-2,4-dione; D000970:Antineoplastic Agents; D051246:Glucose Transport Proteins, Facilitative; D051272:Glucose Transporter Type 1; D047495:PPAR gamma; D045162:Thiazolidinediones