Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361005, China.
Department of Chemistry and Key Laboratory of Chemical Biology of Fujian Province, iChEM, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, China.
J Med Chem. 2020 Jun 11;63(11):5841-5855. doi: 10.1021/acs.jmedchem.0c00088. Epub 2020 May 28.
We reported recently that (), 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 of with RXRα by design, synthesis, and biological evaluation of a focused library of 15 novel analogues. Among them, 3,9-dimethoxy-5,6-dihydroisoquinolino[3,2-]isoquinolin-7-ium chloride () was identified as the optimal RXRα activator. More efficiently than , bound and altered the conformation of RXRα/LBD, thereby suppressing the Wnt/β-catenin pathway and colon cancer cell growth via RXRα mediation. In addition, not only preserved 's tumor selectivity but also greatly improved its bioavailability. Remarkably, in mice, did 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 of -derived RXRα activators as novel effective antineoplastic agents for colon cancer.
我们最近报道称，（），一种治疗肠胃炎的传统东方药物，通过设计、合成和生物评价一个针对 RXRα 的聚焦文库的 15 种新型（）类似物，基于与 RXRα 的结合模式扩展了我们的研究。其中，3,9-二甲氧基-5,6-二氢异喹啉并[3,2-]异喹啉-7-𬭩氯化物（）被鉴定为最佳的 RXRα 激活剂。与（）相比，（）更有效地结合并改变了 RXRα/LBD 的构象，从而通过 RXRα 介导抑制 Wnt/β-连环蛋白通路和结肠癌细胞生长。此外，（）不仅保留了（）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，（）没有表现出明显的副作用，包括其他 RXRα 激动剂引起的高甘油三酯血症或肝肾功能毒性。总之，我们的研究描述了一种基于（）衍生的 RXRα 激活剂的合理设计方法，作为治疗结肠癌的新型有效抗肿瘤药物。
