Synthesis and Structure–Activity Relationships of N-Dihydrocoptisine-8-ylidene Aromatic Amines and N-Dihydrocoptisine-8-ylidene Aliphatic Amides as Antiulcerative Colitis Agents Targeting XBP1

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• 作者：Meng Xie ; Hai-Jing Zhang ; An-Jun Deng ; Lian-Qiu Wu ; Zhi-Hui Zhang ; Zhi-Hong Li ; Wen-Jie Wang ; Hai-Lin Qin
• 刊名：Journal of Natural Products
• 出版年：2016
• 出版时间：April 22, 2016
• 年：2016
• 卷：79
• 期：4
• 页码：775-783
• 全文大小：410K
• 年卷期：0
• ISSN：1520-6025

文摘

In this study, natural quaternary coptisine was used as a lead compound to design and synthesize structurally stable and actively potent coptisine analogues. Of the synthesized library, 13 N-dihydrocoptisine-8-ylidene amines/amides were found not only to be noncytotoxic toward intestinal epithelial cells (IECs), but they were also able to activate the transcription of X-box-binding protein 1 (XBP1) targets to varying extents in vitro. Antiulcerative colitis (UC) activity levels were assessed at the in vitro molecular level as well as in vivo in animals using multiple biomarkers as indices. In an in vitro XBP1 transcriptional activity assay, four compounds demonstrated good dose–effect relationships with EC₅₀ values of 0.0708–0.0132 μM. Moreover, two compounds were confirmed to be more potent in vivo than a positive control, demonstrating a curative effect for UC in experimental animals. Thus, the findings of this study suggest that these coptisine analogues are promising candidates for the development of anti-UC drugs.