Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, 336 Parks Hall, 500 West 12th Avenue, Columbus, Ohio 43210, USA.
J Med Chem. 2010 Mar 25;53(6):2552-61. doi: 10.1021/jm901773d.
In light of the unique ability of thiazolidinediones to mediate peroxisome proliferator-activated receptor (PPAR)gamma-independent activation of adenosine monophosphate-activated protein kinase (AMPK) and suppression of interleukin (IL)-6 production, we conducted a screening of an in-house, thiazolidinedione-based focused compound library to identify novel agents with these dual pharmacological activities. Cell-based assays pertinent to the activation status of AMPK and mammalian homologue of target of rapamycin (i.e., phosphorylation of AMPK and p70 ribosomal protein S6 kinase, respectively) and IL-6/IL-6 receptor signaling (i.e., IL-6 production and signal transducer and activator of transcription 3 phosphorylation, respectively) in lipopolysaccharide (LPS)-stimulated THP-1 human macrophages were used to screen this compound library, which led to the identification of compound 53 (N-{4-[3-(1-methyl-cyclohexylmethyl)-2,4-dioxo-thiazolidin-5-ylidene-methyl]-phenyl}-4-nitro-3-trifluoro-methyl-benzenesulfonamide) as the lead agent. Evidence indicates that this drug-induced suppression of LPS-stimulated IL-6 production was attributable to AMPK activation. Furthermore, compound 53-mediated AMPK activation was demonstrated in C-26 colon adenocarcinoma cells, indicating that it is not a cell line-specific event.
鉴于噻唑烷二酮具有独特的能力，可以介导过氧化物酶体增殖物激活受体 (PPAR)γ 非依赖性激活腺苷单磷酸激活蛋白激酶 (AMPK) 并抑制白细胞介素 (IL)-6 的产生，我们对内部基于噻唑烷二酮的聚焦化合物库进行了筛选，以寻找具有这些双重药理活性的新型药物。基于细胞的测定法与 AMPK 的激活状态以及哺乳动物雷帕霉素靶蛋白的同源物（即分别为 AMPK 和 p70 核糖体蛋白 S6 激酶的磷酸化）以及 IL-6/IL-6 受体信号（即分别为 IL-6 产生和信号转导和转录激活因子 3 的磷酸化）相关，用于筛选该化合物库，这导致了化合物 53（N- {4- [3-（1-甲基环己基甲基）-2,4-二氧代噻唑烷-5-亚基甲基]-苯基} -4-硝基-3-三氟甲基苯磺酰胺）的鉴定作为先导剂。有证据表明，这种药物诱导的 LPS 刺激的 IL-6 产生抑制归因于 AMPK 的激活。此外，在 C-26 结肠腺癌细胞中证实了化合物 53 介导的 AMPK 激活，表明这不是细胞系特异性事件。
