Structure-Activity Relationship Study Enables the Discovery of a Novel Berberine Analogue as the RXR alpha Activator to Inhibit Colon Cancer
Structure-Activity Relationship Study Enables the Discovery of a Novel Berberine Analogue as the RXR alpha Activator to Inhibit Colon Cancer
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结构-活性关系研究发现了一种新型小檗碱类似物作为 RXRα 激活剂来抑制结肠癌
DOI：
10.1021/acs.jmedchem.0c00088
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发表时间：
2020
影响因子：
7.3
通讯作者：
Hu Tianhui
中科院分区：
文献类型：
--
作者：
Xu Beibei;Jiang Xunjin;Xiong Jing;Lan Jun;Tian Yuan;Zhong Linhai;Wang Xinquan;Xu Ning;Cao Hanwei;Zhang Wenqing;Zhang Hao;Hong Xiaoting;Zhan Yan-yan;Zhang Y;ong;Hu Tianhui
我们最近报道了治疗胃肠炎的传统东方药物小檗碱（Berberine，Ber）结合并激活类维生素A X受体α（retinoid X receptor α，RXRα）抑制结肠癌细胞的生长。本论文基于小檗碱与RXRα的结合模式，设计、合成了15个新的小檗碱类似物，并对其进行了生物学评价。其中，3，9-二甲氧基-5，6-二氢异喹啉并[3，2-a]异喹啉-7-鎓氯化物（B-12）被确定为最佳的RXRα激活剂。B-12比Ber更有效地结合并改变RXRα/LBD的构象，从而通过RXRα介导抑制Wnt/β-catenin途径和结肠癌细胞生长。此外，B-12不仅提高了Ber的肿瘤选择性，而且大大提高了其生物利用度。值得注意的是，在小鼠中，B-12没有表现出像其他RXRα激动剂那样的明显副作用，包括高血糖症或引起肝肾毒性。总之，我们的研究描述了一种合理设计Ber-derived RXRα激活剂作为结肠癌新型有效抑制剂的方法。
We reported recently thatberberine(Ber), a traditional oriental medicine to treat gastroenteritis, binds and activates retinoid X receptor α (RXRα) for suppressing the growth of colon cancer cells. Here, we extended our studies based on the binding mode ofBerwith RXRα by design, synthesis, and biological evaluation of a focused library of 15 novelBeranalogues. Among them, 3,9-dimethoxy-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium chloride (B-12) was identified as the optimal RXRα activator. More efficiently thanBer,B-12bound and altered the conformation of RXRα/LBD, thereby suppressing the Wnt/β-catenin pathway and colon cancer cell growth via RXRα mediation. In addition,B-12not only preservedBer’s tumor selectivity but also greatly improved its bioavailability. Remarkably, in mice,B-12did not show obvious side effects including hypertriglyceridemia as other RXRα agonists or induce hepatorenal toxicity. Together, our study describes an approach for the rational design ofBer-derived RXRα activators as novel effective antineoplastic agents for colon cancer.