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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Wang D,Chu PC,Yang CN,Yan R,Chuang YC,Kulp SK,Chen CSdoi
10.1021/jm300015msubject
Has Abstractpub_date
2012-04-26 00:00:00pages
3827-36issue
8eissn
0022-2623issn
1520-4804journal_volume
55pub_type
杂志文章,收录出版abstract：:A series of 80 7-(het)aryl- and 7-ethynyl-7-deazapurine ribonucleosides bearing a methoxy, methylsulfanyl, methylamino, dimethylamino, methyl, or oxo group at position 6, or 2,6-disubstituted derivatives bearing a methyl or amino group at position 2, were prepared, and the biological activity of the compounds was stud...
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
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更新日期：2015-08-13 00:00:00
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更新日期：2015-01-22 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
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abstract：:N-Methyl-d-aspartate (NMDA) receptor dysfunction has been linked to several neuropsychiatric disorders, including Alzheimer's disease, epilepsy, drug addiction, and schizophrenia. A radioligand that could be used with PET to image and quantify human brain NMDA receptors in the activated "open channel" state would be u...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b01510
更新日期：2015-12-24 00:00:00
