jm7b00282_si_002.csv (1.97 kB)
Design, Synthesis, and Evaluation of Thiazolidine-2,4-dione Derivatives as a Novel Class of Glutaminase Inhibitors
dataset
posted on 2017-06-13, 00:00 authored by 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 LeeHumans have two glutaminase genes, GLS (GLS1) and GLS2, each
of which has two alternative
transcripts: the kidney isoform (KGA) and glutaminase C (GAC) for GLS, and the liver isoform (LGA) and glutaminase B (GAB)
for GLS2. Initial hit compound (Z)-5-((1-(4-bromophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)methylene)thiazolidine-2,4-dione
(2), 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.