黄连碱
化学
药效团
溃疡性结肠炎
XBP1型
体内
体外
结肠炎
药理学
生物活性
生物化学
立体化学
小檗碱
内科学
免疫学
生物
生物技术
基因
医学
巴马汀
疾病
核糖核酸
RNA剪接
作者
Zhihui Zhang,Hai-Jing Zhang,An-Jun Deng,Bo Wang,Zhihong Li,Yang Liu,Li-Wei Wu,Wenjie Wang,Hai-Lin Qin
标识
DOI:10.1021/acs.jmedchem.5b00964
摘要
Thirty quaternary coptisine derivatives from a synthesized library were found to activate the in vitro transcription of x-box-binding protein 1 (XBP1). Among these, the dihydrocoptisines were demonstrated by in vitro XBP1 transcriptional activity assays and animal experiments to be much more active anti-ulcerative colitis (UC) agents than quaternary coptisines, tetrahydrocoptisines, and the positive control. Unsubstituted dihydrocoptisine exhibited more significant anti-UC efficacy than dihydrocoptisines substituted at the C-8 or C-13 position. The EC50 value of dihydrocoptisine for XBP1 transcriptional activation was 2.25 nM. Dihydrocoptisine exhibited a significant dose-effect relationship, as indicated by biomarkers in in vitro and in vivo experiments. According to this study, the starting material's reductive states and the substitution patterns of the dihydrocoptisines were determined to be the critical parameters for modulating their anti-UC efficacy, and the dihydrocoptisine skeleton was designated as the key pharmacophore. The synthesized dihydrocoptisine is a promising lead for developing anti-UC drugs.
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