BACKGROUND & AIMS: :Native chromatin IP assays were used to define changes in core histone acetylation at the lysozyme locus during developmental maturation of chicken macrophages and stimulation to high-level expression by lipo-polysaccharide. In pluripotent precursors the lysozyme gene (Lys) is inactive and there is no acetylation of core histones at the gene, its promoter or at the upstream cis-control elements. In myeloblasts, where there is a very low level of Lys expression, H4 acetylation appears at the cis-control elements but not at the Lys gene or its promoter: neither H3 nor H2B become significantly acetylated in myeloblasts. In mature macrophages, Lys expression increases 5-fold: H4, H2B and H2A.Z are all acetylated at the cis-control elements but H3 remains unacetylated except at the -2.4 S silencer. Stimulation with LPS increases Lys expression a further 10-fold: this is accompanied by a rise in H3 acetylation throughout the cis-control elements; H4 and H2B acetylation remain substantial but acetylation at the Lys gene and its promoter remains low. Acetylation is thus concentrated at the cis-control elements, not at the Lys gene or its immediate promoter. H4 acetylation precedes H3 acetylation during development and H3 acetylation is most directly linked to high-level Lys expression.

背景与目标： ：天然染色质IP分析用于确定鸡巨噬细胞发育成熟和脂多糖刺激高水平表达期间溶菌酶基因座核心组蛋白乙酰化的变化。在多能的前体中，溶菌酶基因（Lys）是无活性的，并且在该基因，其启动子或上游顺式控制元件上没有核心组蛋白的乙酰化。在成纤维细胞中，Lys表达水平非常低，H4乙酰化出现在顺式控制元件上，而没有出现在Lys基因或其启动子上：H3和H2B在成纤维细胞中都没有被显着乙酰化。在成熟的巨噬细胞中，Lys表达增加5倍：H4，H2B和H2A.Z在顺式控制元件上均被乙酰化，但H3除外-2.4 S沉默子上保持未乙酰化。用LPS刺激可将Lys表达进一步提高10倍：伴随着整个顺式控制元件中H3乙酰化的增加； H4和H2B的乙酰化作用仍然很强，但Lys基因及其启动子的乙酰化作用仍然很低。因此，乙酰化作用集中在顺式控制元件上，而不是Lys基因或其直接启动子上。在发育过程中，H4乙酰化先于H3乙酰化，而H3乙酰化与高水平Lys表达最直接相关。

BACKGROUND & AIMS: :The alkenyldiarylmethanes (ADAMs) are a unique class of non-nucleoside reverse transcriptase inhibitors that have potential value in the treatment of HIV/AIDS. However, the potential usefulness of the ADAMs is limited by the presence of metabolically labile methyl ester moieties. A series of novel ADAMs were therefore designed and synthesized in order to replace the metabolically labile methyl ester moieties of the existing ADAM lead compounds with hydrolytically stable, fused isoxazolone, isoxazole, oxazolone, or cyano substituents on the aromatic rings. The methyl ester and methoxy substituents on both of the aromatic rings in the parent compound 1 were successfully replaced with metabolically stable moieties with retention of anti-HIV activity and a general decrease in cytotoxicity.

背景与目标： ：烯基二芳基甲烷（ADAM）是一类独特的非核苷类逆转录酶抑制剂，在治疗HIV / AIDS中具有潜在价值。然而，ADAM的潜在用途受到代谢不稳定的甲基酯部分的存在的限制。因此，设计并合成了一系列新颖的ADAM，以在芳香环上用水解稳定的稠合异恶唑酮，异恶唑，恶唑酮或氰基取代基取代现有ADAM铅化合物的代谢不稳定的甲基部分。母体化合物1的两个芳香环上的甲酯和甲氧基取代基均成功地被代谢稳定的部分所取代，并保留了抗HIV活性并普遍降低了细胞毒性。

BACKGROUND & AIMS: :We studied the influence of aprotinin and soya bean trypsin inhibitor (SBTI) on the inflammatory reaction induced by the implantation of dry sponges in normal Wistar rats and in kininogen-deficient Brown Norway rats, during the first day after the implantation. In normal rats, aprotinin reduced the volume and total protein content of the exudates at 3 h but not thereafter. Aprotinin also markedly reduced the immunoreactive kinins and kallikrein in the exudates. Aprotinin did not modify the volume of the exudates of the Brown Norway rats. SBTI reduced the inflammatory reaction in both rat strains but did not significantly modify the formation of immunoreactive kinins. The inflammatory reaction developed more slowly in Brown Norway rats. The kinin system is thus involved during the first hours of the development of this acute inflammatory reaction. The anti-inflammatory effect of SBTI does not depend on the inhibition of kinin formation.

背景与目标： ：我们研究了抑肽酶和大豆胰蛋白酶抑制剂（SBTI）在植入后第一天对正常Wistar大鼠和缺乏激肽原的褐挪威大鼠中植入干海绵诱导的炎症反应的影响。在正常大鼠中，抑肽酶在3小时后降低了分泌液的体积和总蛋白含量，但此后没有降低。抑肽酶还显着降低渗出液中的免疫反应激肽和激肽释放酶。抑肽酶未改变棕色挪威大鼠渗出液的体积。 SBTI减少了两种大鼠品系中的炎症反应，但并未显着改变免疫反应激肽的形成。在布朗挪威大鼠中，炎症反应发展得较慢。因此，激肽系统参与了这种急性炎症反应发展的最初几个小时。 SBTI的抗炎作用不取决于对激肽形成的抑制作用。

BACKGROUND & AIMS: :The fumigant insecticide phosphine (PH3) is known to inhibit cytochrome c oxidase in vitro. Inhibition of the respiratory chain at this site has been shown to stimulate the generation of superoxide radicals (O2-), which dismutate to form hydrogen peroxide (H2O2). This study was performed in order to investigate the production of H2O2 by mitochondria isolated from granary weevil (Sitophilus granarius) and mouse liver on exposure to PH3. Other respiratory inhibitors, antimycin, myxothiazol, and rotenone were used with insect mitochondria. Hydrogen peroxide was measured spectrophotometrically using yeast cytochrome c peroxidase as an indicator. Insect and mouse liver mitochondria, utilizing endogenous substrate, both produced H2O2 after inhibition by PH3. Insect organelles released threefold more H2O2 than did mouse organelles, when exposed to PH3. Production of H2O2 by PH3-treated insect mitochondria was increased significantly on addition of the substrate alpha-glycerophosphate. Succinate did not enhance H2O2 production, however, indicating that the H2O2 did not result from the autoxidation of ubiquinone. NAD(+)-linked substrates, malate and pyruvate also had no effect on H2O2 production, suggesting that NADH-dehydrogenase was not the source of H2O2. Data obtained using antimycin and myxothiazol, both of which stimulated the release of H2O2 from insect mitochondria, lead to the conclusion that glycerophosphate dehydrogenase is a source of H2O2. The effect of combining PH3, antimycin, and myxothiazol on cytochrome spectra in insect mitochondria was also recorded. It was observed that PH3 reduces cytochrome c oxidase but none of the other cytochromes in the electron transport chain. There was no movement of electrons to cytochrome b when insect mitochondria are inhibited with PH3. The spectral data show that the inhibitors interact with the respiratory chain in a way that would allow the production of H2O2 from the sites proposed previously.

背景与目标： ：已知熏蒸杀虫剂膦（PH3）在体外可抑制细胞色素C氧化酶。已显示出在该部位抑制呼吸链会刺激超氧化物自由基（O2-）的生成，这些自由基会歧化形成过氧化氢（H2O2）。进行这项研究是为了研究暴露于PH3时从粮象鼻虫（Sitophilus granarius）和小鼠肝脏分离的线粒体产生H2O2。其他呼吸抑制剂，抗霉素，甲噻唑和鱼藤酮与昆虫线粒体一起使用。使用酵母细胞色素c过氧化物酶作为指示剂，通过分光光度法测量过氧化氢。昆虫和小鼠肝线粒体利用内源性底物，在被PH3抑制后均产生H2O2。当暴露于PH3时，昆虫细胞器释放的H2O2比小鼠细胞器释放的三倍。加入底物α-甘油磷酸后，PH3处理的昆虫线粒体产生的H2O2显着增加。琥珀酸酯并没有增加H2O2的产生，但是，这表明H2O2不是由泛醌的自氧化作用产生的。 NAD（）连接的底物，苹果酸和丙酮酸也对H2O2的产生没有影响，这表明NADH脱氢酶不是H2O2的来源。使用抗霉素和甲噻唑获得的数据均刺激了昆虫线粒体释放H2O2，得出的结论是甘油磷酸脱氢酶是H2O2的来源。还记录了PH3，抗霉素和Mythothiazol组合对昆虫线粒体中细胞色素光谱的影响。观察到PH3会还原细胞色素c氧化酶，但在电子传输链中没有其他细胞色素。当昆虫线粒体被PH3抑制时，电子不会移动到细​​胞色素b。光谱数据表明，抑制剂与呼吸链相互作用的方式可以使先前提出的位点产生H2O2。

BACKGROUND & AIMS: :Cyclin dependent kinase 5 (CDK5) is a serine/threonine kinase belonging to the cyclin dependent kinase (CDK) family. CDK5 is involved in numerous neuronal diseases (including Alzheimer's or Parkinson's diseases, stroke, traumatic brain injury), pain signaling and cell migration. In the present Letter, we describe syntheses and biological evaluations of new 2,6,9-trisubstituted purines, structurally related to roscovitine, a promising CDK inhibitor currently in clinical trials (CDK1/Cyclin B, IC(50)=350 nM; CDK5/p25, IC(50)=200 nM). These new molecules were synthesized using an original Buchwald-Hartwig catalytic procedure; several compounds (3j, 3k, 3l, 3e, 4k, 6b, 6c) displayed potent kinase inhibitory potencies against CDK5 (IC(50) values ranging from 17 to 50 nM) and showed significant cell death inducing activities (IC(50) values ranging from 2 to 9 μM on SH-SY5Y). The docking of the inhibitors into the ATP binding domain of the CDK5 catalytic site highlighted the discriminatory effect of a hydrogen bond involving the CDK5 Lys-89. In addition, the calculated final energy balances for complexation measured for several inhibitors is consistent with the ranking of the IC(50) values. Lastly, we observed that several compounds exhibit submicromolar activities against DYRK1A (dual specificity, tyrosine phosphorylation regulated kinase 1A), a kinase involved in Down syndrome and Alzheimer's disease (3g, 3h, 4m; IC(50) values ranging from 300 to 400 nM).

背景与目标： ：细胞周期蛋白依赖性激酶5（CDK5）是属于细胞周期蛋白依赖性激酶（CDK）家族的丝氨酸/苏氨酸激酶。 CDK5与多种神经元疾病（包括阿尔茨海默氏症或帕金森氏症，中风，脑外伤），疼痛信号和细胞迁移有关。在本信中，我们描述了新的2,6,9-三取代嘌呤的合成和生物学评估，这些嘌呤在结构上与roscovitine有关，roscovitine是目前在临床试验中有希望的CDK抑制剂（CDK1 / Cyclin B，IC（50）= 350 nM; CDK5 / p25，IC（50）= 200 nM）。这些新分子是使用原始的Buchwald-Hartwig催化程序合成的；几种化合物（3j，3k，3l，3e，4k，6b，6c）对CDK5表现出有效的激酶抑制作用（IC（50）值为17至50 nM），并显示出显着的细胞死亡诱导活性（IC（50）值） SH-SY5Y的范围为2至9μM）。抑制剂对接至CDK5催化位点的ATP结合域中，突显了涉及CDK5 Lys-89的氢键的歧视性作用。此外，针对几种抑制剂测得的络合最终能量平衡计算结果与IC（50）值的排名一致。最后，我们观察到几种化合物对DYRK1A表现出亚微摩尔活性（双重特异性，酪氨酸磷酸化调节激酶1A），该激酶与唐氏综合症和阿尔茨海默氏病有关（3g，3h，4m； IC（50）值介于300至400 nM之间）。

BACKGROUND & AIMS: :DNA double strand breaks need to be repaired in an organized fashion to preserve genomic integrity. In the organization of faithful repair, histone ubiquitination plays a crucial role. Recent findings suggest an integrated model for DNA repair regulation through site-specific histone ubiquitination and crosstalk to other posttranslational modifications. Here we discuss how site-specific histone ubiquitination is achieved on a molecular level and how different multi-protein complexes work together to integrate different histone ubiquitination states. We propose a model where site-specific H2A ubiquitination organizes the spatio-temporal recruitment of DNA repair factors which will ultimately contribute to DNA repair pathway choice between homologous recombination and non-homologous end joining.

背景与目标： ：DNA双链断裂需要以有组织的方式进行修复，以保持基因组完整性。在忠实修复的组织中，组蛋白泛素化起着至关重要的作用。最近的发现表明，通过位点特异性组蛋白泛素化和串扰与其他翻译后修饰的DNA修复调控的集成模型。在这里，我们讨论如何在分子水平上实现位点特异性组蛋白泛素化，以及不同的多蛋白复合物如何协同工作以整合不同的组蛋白泛素化状态。我们提出了一个模型，在该模型中，位点特异性H2A泛素化组织了DNA修复因子的时空募集，最终将促成DNA修复途径在同源重组和非同源末端连接之间的选择。

BACKGROUND & AIMS: :A series of novel resveratrol derivatives were designed, synthesised and evaluated as potential therapeutic agents for the treatment of Alzheimer's disease. Among these compounds, compound 7l, (E)-5-(4-(isopropylamino)styryl)benzene-1,3-diol, exhibited potent ß-amyloid aggregation inhibition activity, which was confirmed by a ThT fluorescence assay (71.65% at 20 μM) and transmission electron microscopy (TEM). Compound 7l also exhibited good antioxidant activity (4.12 Trolox equivalents in an oxygen radical absorbance capacity assay and a 37% reduction in reactive oxygen species in cells at 10 μM). The cytotoxicity analysis of compounds 7f, 7i, 7j and 7l indicated that these compounds have lower toxicities than resveratrol at 60 μM.

背景与目标： ：设计，合成和评估了一系列新型白藜芦醇衍生物，作为治疗阿尔茨海默氏病的潜在治疗剂。在这些化合物中，化合物7l，（E）-5-（4-（异丙基氨基）苯乙烯基）苯-1,3-二醇表现出强力的β-淀粉样蛋白聚集抑制活性，这可通过ThT荧光测定法证实（71.65％在20μM）和透射电子显微镜（TEM）。化合物7-1也表现出良好的抗氧化活性（在氧自由基吸收能力测定中为4.12 Trolox当量，并且在10μM下细胞中的活性氧减少了37％）。化合物7f，7i，7j和7l的细胞毒性分析表明，在60μM浓度下，这些化合物的毒性低于白藜芦醇。

BACKGROUND & AIMS: :A novel series of potent and efficacious factor Xa inhibitors which possesses sulfoximine moiety as novel S4 binding element in anthranilamide chemotype has been identified. Lead optimization at this novel P4 group led to many potent factor Xa inhibitors with excellent anticoagulant activity in human plasma. Selected compounds were dosed orally in rats and checked for their ex vivo prothrombin time prolonging activity, which resulted in identification of compound 5-chloro-N-(5-chloropyridin-2-yl)-2-(4-(N-(2-(diethylamino)acetyl)-S-methylsulfonimidoyl)benzamido)benzamide (18f). The detailed pharmacokinetic evaluation and subsequent metabolism study of 18f suggested the presence of an active metabolite. The compound 18f and its active metabolite 18b demonstrated excellent in vivo efficacy in both arterial and venous thrombosis model in rats and were found to be highly selective against related serine proteases. Based on this promising profile, compound 18f was selected for further evaluation.

背景与目标： ：已鉴定出一系列新的有效且有效的因子Xa抑制剂，其具有硫肟亚胺部分作为邻氨基苯甲酰胺化学型中的新型S4结合元件。在这个新颖的P4组中进行的前导优化导致了许多有效的Xa抑制剂在人血浆中具有出色的抗凝活性。在大鼠中口服选择的化合物并检查其离体凝血酶原时间延长活性，从而鉴定出化合物5-氯-N-（5-氯吡啶-2-基）-2-（4-（N-（2 -（二乙氨基）乙酰基）-S-甲基磺酰亚胺基）苯甲酰胺基）苯甲酰胺（18f）。 18f的详细药代动力学评估和随后的代谢研究表明存在活性代谢物。化合物18f及其活性代谢物18b在大鼠的动脉和静脉血栓形成模型中均显示出优异的体内功效，并且被发现对相关的丝氨酸蛋白酶具有高度选择性。基于这一有前途的概况，选择了化合物18f进行进一步评估。

BACKGROUND & AIMS: :As a continuation of our efforts directed towards the development of anti-diabetic agents from natural sources, piplartine was isolated from Piper chaba, and was found to inhibit recombinant human ALR2 with an IC(50) of 160 μM. To improve the efficacy, a series of analogues have been synthesized by modification of the styryl/aromatic and heterocyclic ring functionalities of this natural product lead. All the derivatives were tested for their ALR2 inhibitory activity, and results indicated that adducts 3c, 3e and 2j prepared by the Michael addition of piplartine with indole derivatives displayed potent ARI activity, while the other compounds displayed varying degrees of inhibition. The active compounds were also capable of preventing sorbitol accumulation in human red blood cells.

背景与目标： ：作为我们致力于从天然来源开发抗糖尿病药的努力的继续，从哌派（Piper chaba）分离了吡哌汀，并发现其抑制重组人ALR2的IC（50）为160μM。为了提高功效，已经通过修饰该天然产物铅的苯乙烯基/芳族和杂环官能团合成了一系列类似物。测试了所有衍生物的ALR2抑制活性，结果表明，通过迈克尔·匹普汀与吲哚衍生物的迈克尔加成反应制备的加合物3c，3e和2j具有较强的ARI活性，而其他化合物则表现出不同程度的抑制作用。活性化合物还能够防止山梨糖醇在人红细胞中积累。

BACKGROUND & AIMS: :Sensitizing mutations in the epidermal growth factor receptor (EGFR) predict response to EGFR tyrosine kinase inhibitors (TKIs) and both first- and second-generation TKIs are available as first-line treatment options in patients with advanced EGFR-mutant non-small cell lung cancer. Eventual resistance develops with multiple mechanisms identifiable both upon repeat biopsy and in plasma circulating tumor DNA. The T790M gatekeeper mutation is responsible for almost 60% of cases. A number of third-generation TKIs are in clinical development, and osimertinib has been approved by the US Food and Drug Administration for the treatment of patients with EGFR T790M mutant lung cancer after failure of initial EGFR kinase therapy. Resistance mechanisms are being identified to these novel agents, and the treatment landscape of EGFR-mutant lung cancer continues to evolve. The sequence of EGFR TKIs may change in the future and combination therapies targeting resistance appear highly promising.

背景与目标： ：表皮生长因子受体（EGFR）中的致敏突变预测对EGFR酪氨酸激酶抑制剂（TKIs）的反应，对于晚期EGFR突变的非小细胞患者，第一代和第二代TKI均可作为一线治疗选择肺癌。最终的耐药性会通过重复活检和血浆循环肿瘤DNA鉴定出多种机制发展。 T790M Gatekeeper突变负责将近60％的病例。许多第三代TKI正在临床开发中，奥西替尼已被美国食品和药物管理局批准用于治疗初始EGFR激酶治疗失败后的EGFR T790M突变型肺癌患者。人们已经确定了对这些新型药物的耐药机制，EGFR突变型肺癌的治疗前景也在不断发展。 EGFR TKIs的序列可能会在未来发生变化，针对耐药性的联合疗法似乎很有希望。

BACKGROUND & AIMS: :Two new families of human farnesyltransferase inhibitors 13a-m and 14a-d, based on a phenothiazine scaffold, were synthesized. Compounds 14a and 14b were the most promising inhibitors of human farnesyltransferase with IC(50) values of 0.7 and 0.6 μM, respectively.

背景与目标： ：基于吩噻嗪支架，合成了两个新的人类法呢基转移酶抑制剂家族13a-m和14a-d。化合物14a和14b是人类法呢基转移酶的最有希望的抑制剂，其IC（50）值分别为0.7和0.6μM。

BACKGROUND & AIMS: :Utilizing X-ray crystal structure analysis, (3S,5R)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]piperidine-3-carboxamides were designed and identified as renin inhibitors. The most potent compound 15 demonstrated favorable pharmacokinetic and pharmacodynamic profiles in rat.

背景与目标： ：利用X射线晶体结构分析，设计了（3S，5R）-5- [4-（2-氯苯基）-2,2-二甲基-5-氧哌嗪-1-基]哌啶-3-甲酰胺，并将其鉴定为肾素抑制剂。最有效的化合物15在大鼠中显示出良好的药代动力学和药效学特征。

BACKGROUND & AIMS: :A study in mice suggests that macrophages produce resistance to checkpoint inhibitors by removing anti-PD-1 antibodies from T cells. Fcγ receptors on macrophages bind to the Fc domain on the antibodies. Blocking this interaction with other antibodies produced dramatic tumor shrinkage in mice.

背景与目标： ：在小鼠中的一项研究表明，巨噬细胞通过从T细胞中去除抗PD-1抗体来产生对检查点抑制剂的抗性。巨噬细胞上的Fcγ受体与抗体上的Fc结构域结合。阻断与其他抗体的这种相互作用会在小鼠中产生明显的肿瘤缩小。

BACKGROUND & AIMS: PURPOSE:In the regulation of chromatin-structure and histone function, histone deacetylases (HDACs) are key enzymes and thus modulators of epigenetic regulation and gene expression. Accesses of the HDAC inhibitor vorinostat to intracellular compartments are essential to exert epigenetic effects. METHODS:In ten sarcoma patients receiving oral Zolinza (400 mg qd) vorinostat concentrations in plasma and peripheral blood mononuclear cells (PBMCs) were quantified using validated LC/MS/MS assays to determine intracellular and extracellular pharmacokinetic data. Cellular HDAC activity was evaluated using a fluorogenic assay. Concentration-response relationships were established between intracellular and extracellular vorinostat concentrations and HDAC inhibition in PBMCs. RESULTS:Pharmacokinetics of vorinostat and its two main inactive metabolites were determined over 8 h in plasma and PBMCs. Steady state AUCs (±SD) and T1/2 (±SD) were calculated to 4.61 ± 0.87 h µM and 1.73 ± 0.69 h (plasma) and 15.2 ± 9.03 h µM and 5.30 ± 4.27 h (PBMCs). Intracellular accumulation of vorinostat was determined together with prolonged vorinostat elimination in PBMCs. Cellular HDAC inhibition increased parallel with vorinostat concentrations in plasma and PBMCs. For effective inhibition of cellular HDACs (IC50) vorinostat concentrations of 0.05 µM in plasma and 0.17 µM in PBMCs were necessary. CONCLUSION:HDAC inhibition closely followed intracellular vorinostat concentrations and was short-lasting, which may contribute to the limited efficacy seen with vorinostat in solid tumors so far.

背景与目标： 目的：在染色质结构和组蛋白功能的调节中，组蛋白脱乙酰基酶（HDACs）是关键酶，因此是表观遗传调节和基因表达的调节剂。 HDAC抑制剂伏立诺他进入细胞内区室对于发挥表观遗传学作用至关重要。
方法：使用经验证的LC / MS / MS测定法对接受口服Zolinza（400 mg qd）血浆和外周血单核细胞（PBMC）浓度的伏立诺司他浓度的10例肉瘤患者进行定量，以确定细胞内和细胞外药代动力学数据。使用荧光测定法评估细胞的HDAC活性。 PBMC中细胞内和细胞外伏立诺他浓度与HDAC抑制之间建立了浓度-反应关系。
结果：伏立诺他及其两种主要的非活性代谢产物在8小时内在血浆和PBMC中的药代动力学被确定。稳态AUC（±SD）和T1 / 2（±SD）计算为4.61±0.87 h M和1.73±0.69 h（血浆）和15.2±9.03 h µM和5.30±4.27 h（PBMC）。确定了伏立诺他在PBMC中的细胞内蓄积以及伏立诺他的长期消除。细胞HDAC抑制与血浆和PBMC中的伏立诺他浓度平行增加。为了有效抑制细胞HDAC（IC50），需要使用伏立诺司他在血浆中的浓度为0.05 µM，在PBMC中的浓度为0.17 µM。
结论：HDAC的抑制作用与细胞内伏立诺他浓度密切相关且持续时间短，这可能是迄今为止迄今为止在实体瘤中伏立诺他所见疗效有限的原因。

BACKGROUND & AIMS: :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.

背景与目标： ：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（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生成；（2）通过药代动力学研究显示血浆中高浓度暴露；（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。