Synthesis and Structure鈥揂ctivity Relationships of Quaternary Coptisine Derivatives as Potential Anti-ulcerative Colitis Agents
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- 作者：Zhi-Hui Zhang ; Hai-Jing Zhang ; An-Jun Deng ; Bo Wang ; Zhi-Hong Li ; Yang Liu ; Lian-Qiu Wu ; Wen-Jie Wang ; Hai-Lin Qin
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：September 24, 2015
- 年：2015
- 卷：58
- 期：18
- 页码：7557-7571
- 全文大小：631K
- ISSN：1520-4804
文摘
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鈥揺ffect relationship, as indicated by biomarkers in in vitro and in vivo experiments. According to this study, the starting material鈥檚 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.