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.

译文

:人类有两个谷氨酰胺酶基因,GLS(GLS1)和GLS2,每个都有两个替代转录物:GLS的肾脏同种型(KGA)和谷氨酰胺酶C(GAC),肝脏同种型(LGA)和谷氨酰胺酶B(GAB)适用于GLS2。初始命中化合物(Z)-5-(((1-(4-溴苯基)-2,5-二甲基-1H-吡咯-3-基)亚甲基)噻唑烷-2,4-二酮(2),噻唑烷-2通过对KGA筛选40000种化合物的高通量筛选获得了4-4-二酮。随后,合成了一系列噻唑烷-2,4-二酮衍生物。发现其中大多数可抑制KGA和GAC的活性相当,对GAB的抑制作用较弱,并且对GLS1的选择性比对GLS2的中等。研究了化学结构,活性和选择性之间的关系。发现获得的先导化合物具有(1)提供体外细胞活性以抑制细胞生长,克隆形成和细胞谷氨酸的产生;(2)通过药代动力学研究显示血浆中的高浓度暴露;以及(3)减小肿瘤大小小鼠体内异种移植人胰腺AsPC-1癌细胞的表达。

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