Design, synthesis, and evaluation of thiazolidine-2, 4-dione derivatives as a novel class of glutaminase inhibitors
TK Yeh, CC Kuo, YZ Lee, YY Ke, KF Chu… - Journal of Medicinal …, 2017 - ACS Publications
Journal of Medicinal Chemistry, 2017•ACS Publications
Humans 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-1 H-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 …
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-1 H-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 …
Humans 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.
ACS Publications
以上显示的是最相近的搜索结果。 查看全部搜索结果