Structure–Activity Relationship Study Enables the Discovery of a Novel Berberine Analogue as the RXRα Activator to Inhibit Colon Cancer

We reported recently that berberine (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 of Ber with RXRα by design, synthesis, and biological evaluation of a focused library of 15 novel Ber analogues. 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 than Ber, B-12 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, B-12 not only preserved Ber’s tumor selectivity but also greatly improved its bioavailability. Remarkably, in mice, B-12 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 Ber-derived RXRα activators as novel effective antineoplastic agents for colon cancer.我们此前曾报道，用于治疗胃肠炎的传统东方药物小檗碱（berberine, Ber）可结合并激活视黄醇X受体α（retinoid X receptor α, RXRα），进而抑制结肠癌细胞的增殖。本研究基于小檗碱与RXRα的结合模式，通过设计、合成及生物学评价构建了包含15个新型小檗碱类似物的聚焦化合物库。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）被鉴定为最优的RXRα激活剂。相较于小檗碱，B-12能更高效地结合并改变RXRα配体结合域（Ligand Binding Domain, LBD）的构象，进而通过RXRα介导抑制Wnt/β-连环蛋白（Wnt/β-catenin）信号通路与结肠癌细胞增殖。此外，B-12不仅保留了小檗碱的肿瘤选择性，还显著提升了其生物利用度。值得注意的是，在小鼠模型中，B-12未出现其他RXRα激动剂常见的包括高甘油三酯血症在内的明显不良反应，亦未诱发肝肾毒性。综上，本研究提出了一种合理设计小檗碱衍生RXRα激活剂的策略，有望作为治疗结肠癌的新型高效抗肿瘤药物。