Design, Synthesis,
and Evaluation of Thiazolidine-2,4-dione
Derivatives as a Novel Class of Glutaminase Inhibitors
Teng-Kuang Yeh
Ching-Chuan Kuo
Yue-Zhi Lee
Yi-Yu Ke
Kuang-Feng Chu
Hsing-Yu Hsu
Hsin-Yu Chang
Yu-Wei Liu
Jen-Shin Song
Cheng-Wei Yang
Li-Mei Lin
Manwu Sun
Szu-Huei Wu
Po-Chu Kuo
Chuan Shih
Chiung-Tong Chen
Lun Kelvin Tsou
Shiow-Ju Lee
10.1021/acs.jmedchem.7b00282.s002
https://acs.figshare.com/articles/dataset/Design_Synthesis_and_Evaluation_of_Thiazolidine-2_4-dione_Derivatives_as_a_Novel_Class_of_Glutaminase_Inhibitors/5155777
Humans have two glutaminase genes, <i>GLS</i> (<i>GLS1</i>) and <i>GLS2</i>, each
of which has two alternative
transcripts: the kidney isoform (KGA) and glutaminase C (GAC) for <i>GLS</i>, and the liver isoform (LGA) and glutaminase B (GAB)
for <i>GLS2</i>. Initial hit compound (<i>Z</i>)-5-((1-(4-bromophenyl)-2,5-dimethyl-1<i>H</i>-pyrrol-3-yl)methylene)thiazolidine-2,4-dione
(<b>2</b>), a thiazolidine-2,4-dione, was obtained from a high
throughput screening of 40 000 compounds against KGA. Subsequently,
a series of thiazolidine-2,4-dione derivatives was synthesized. Most
of these were found to inhibit KGA and GAC with comparable activities,
were less potent inhibitors of GAB, and were moderately selective
for GLS1 over GLS2. The relationships between chemical structure,
activity, and selectivity were investigated. The lead compounds obtained
were found to (1) offer in vitro cellular activities for inhibiting
cell growth, clonogenicity, and
cellular glutamate production, (2) exhibit high concentrations of
exposure in plasma by a pharmacokinetic study, and (3) reduce the
tumor size of xenografted human pancreatic AsPC-1 carcinoma cells
in mice.
2017-06-13 00:00:00
GLS 1
GLS 2
Glutaminase Inhibitors Humans
LGA
glutaminase
GAC
GAB
40 000 compounds
KGA