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喹喔啉衍生物的合成及作为 ASK1 抑制剂的生物评价。

Synthesis and biological evaluation of quinoxaline derivatives as ASK1 inhibitors.

机构信息

Jiangxi Provincial Key Laboratory of TCM Female Reproductive Health and Related Diseases Research and Transformation, Jiangxi University of Chinese Medicine, Nanchang, PR China.

College of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, PR China.

出版信息

J Enzyme Inhib Med Chem. 2024 Dec;39(1):2414382. doi: 10.1080/14756366.2024.2414382. Epub 2024 Oct 21.

DOI:10.1080/14756366.2024.2414382
PMID:39431736
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11494716/
Abstract

Inhibiting apoptosis signal regulated kinase 1 (ASK1) is an attractive strategy for treating diseases such as non-alcoholic steatohepatitis and multiple sclerosis. Here, we report the discovery of a dibromo substituted quinoxaline fragment containing as an effective small-molecule inhibitor of ASK1, with an IC value of 30.17 nM. In addition, the cell survival rate of at different concentrations was greater than 80%, especially at 0.4 μM. Its cell survival rate was significantly higher than , indicating its good safety in normal human liver LO2 cells. The Oil Red O staining experiment showed that decreased the lipid droplets in a dose-dependent manner. Further biochemical analyses revealed that could reduce the content of T-CHO, LDL, and TG in FFA-induced LO2 cells, and had the potential to treat non-alcoholic fatty disease. These findings provide a good choice for the future development of ASK1 inhibitors.

摘要

抑制凋亡信号调节激酶 1（ASK1）是治疗非酒精性脂肪性肝炎和多发性硬化症等疾病的一种有吸引力的策略。在这里，我们报告了发现一种二溴取代的喹喔啉片段，其中 是 ASK1 的有效小分子抑制剂，IC 值为 30.17 nM。此外，在不同浓度下， 的细胞存活率均大于 80%，特别是在 0.4 μM 时。其细胞存活率明显高于 ，表明其在正常人肝 LO2 细胞中具有良好的安全性。油红 O 染色实验表明， 呈剂量依赖性降低脂滴。进一步的生化分析表明， 可降低 FFA 诱导的 LO2 细胞中 T-CHO、LDL 和 TG 的含量，有治疗非酒精性脂肪性疾病的潜力。这些发现为 ASK1 抑制剂的未来发展提供了一个很好的选择。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c424/11494716/0d0f18da8e47/IENZ_A_2414382_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c424/11494716/8706b49cbf29/IENZ_A_2414382_UF0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c424/11494716/efa3b8df6121/IENZ_A_2414382_F0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c424/11494716/be32dc929710/IENZ_A_2414382_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c424/11494716/cc77296d8260/IENZ_A_2414382_SCH0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c424/11494716/db36b3219953/IENZ_A_2414382_SCH0002_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c424/11494716/e1cbccff9fe4/IENZ_A_2414382_SCH0003_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c424/11494716/9b5eb8772a6c/IENZ_A_2414382_SCH0004_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c424/11494716/5896977fdabd/IENZ_A_2414382_F0003_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c424/11494716/46f6fb8459a3/IENZ_A_2414382_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c424/11494716/b54366c07366/IENZ_A_2414382_F0005_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c424/11494716/0d0f18da8e47/IENZ_A_2414382_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c424/11494716/8706b49cbf29/IENZ_A_2414382_UF0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c424/11494716/efa3b8df6121/IENZ_A_2414382_F0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c424/11494716/be32dc929710/IENZ_A_2414382_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c424/11494716/cc77296d8260/IENZ_A_2414382_SCH0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c424/11494716/db36b3219953/IENZ_A_2414382_SCH0002_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c424/11494716/e1cbccff9fe4/IENZ_A_2414382_SCH0003_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c424/11494716/9b5eb8772a6c/IENZ_A_2414382_SCH0004_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c424/11494716/5896977fdabd/IENZ_A_2414382_F0003_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c424/11494716/46f6fb8459a3/IENZ_A_2414382_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c424/11494716/b54366c07366/IENZ_A_2414382_F0005_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c424/11494716/0d0f18da8e47/IENZ_A_2414382_F0006_C.jpg

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