Discovery of Novel Imidazo[4,5-c]quinoline Derivatives to Treat Inflammatory Bowel Disease (IBD) by Inhibiting Multiple Proinflammatory Signaling Pathways and Restoring Intestinal Homeostasis.
Discovery of Novel Imidazo[4,5-c]quinoline Derivatives to Treat Inflammatory Bowel Disease (IBD) by Inhibiting Multiple Proinflammatory Signaling Pathways and Restoring Intestinal Homeostasis.
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DOI：
10.1021/acs.jmedchem.2c00390
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发表时间：
2022-09
影响因子：
7.3
通讯作者：
Xuewu Liang;Yong-can Xie;Xuyi Liu;Hui Xu;Hairu Ren;Shuai Tang;Qi Liu;Min Huang;Xueqing Shao;Chunpu Li;Yu Zhou;M. Geng;Zuoquan Xie;Hong Liu
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作者：
Xuewu Liang;Yong-can Xie;Xuyi Liu;Hui Xu;Hairu Ren;Shuai Tang;Qi Liu;Min Huang;Xueqing Shao;Chunpu Li;Yu Zhou;M. Geng;Zuoquan Xie;Hong Liu
炎症性肠病（inflammatory bowel disease，IBD）是一种由免疫炎症因子和肠道菌群共同驱动的复杂发病机制，其治疗可能依赖于对这些重要致病因子的综合调控才能达到良好的治疗效果。在本研究中，我们发现了一系列咪唑并[4，5-c]喹啉衍生物，它们可以有效地同时抑制两种主要的促炎信号通路JAK/STAT和NF-κB。特别地，先导化合物8l显示出对干扰素刺激的基因（IC 50：3.3 nM）和NF-κB途径（IC 50：150.7 nM）的有效抑制活性，并且在纳摩尔水平下减少各种促炎因子的释放，包括IL-6、IL-8、IL-1β、TNF-α、IL-12和IFN-γ。在体内，8l在葡聚糖硫酸钠（DSS）和2，4，6-三硝基苯磺酸（TNBS）诱导的急性肠炎模型中均产生强抗炎活性，并恢复肠道微生物群的结构组成。总的来说，这项研究为IBD的治疗提供了有价值的先导化合物，并揭示了同时抑制JAK/STAT和NF-κB信号的巨大抗炎潜力。
As a complex pathogenesis driven by immune inflammatory factors and intestinal microbiota, the treatment of inflammatory bowel disease (IBD) may rely on the comprehensive regulation of these important pathogenic factors to reach a favorable therapeutic effect. In the current study, we discovered a series of imidazo[4,5-c]quinoline derivatives that potently and simultaneously inhibited two primary proinflammatory signaling pathways JAK/STAT and NF-κB. Especially, lead compound 8l showed potent inhibitory activities against interferon-stimulated genes (IC50: 3.3 nM) and NF-κB pathways (IC50: 150.7 nM) and decreased the release of various proinflammatory factors at the nanomolar level, including IL-6, IL-8, IL-1β, TNF-α, IL-12, and IFN-γ. In vivo, 8l produced a strong anti-inflammatory activity in both dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced acute enteritis models and restored the structural composition of gut microbiota. Collectively, this study provided valuable lead compounds for the treatment of IBD and revealed the great anti-inflammatory potential of the simultaneous suppression of JAK/STAT and NF-κB signals.