Structure–Activity Relationship Study Enables the Discovery of a Novel <b>Berberine</b> Analogue as the RXRα Activator to Inhibit Colon Cancer
Beibei Xu, Xunjin Jiang, Jing Xiong, Jun Lan, Yuan Tian, Linhai Zhong, Xinquan Wang, Ning Xu, Hanwei Cao, Wenqing Zhang, Hao Zhang, Xiaoting Hong, Yan-yan Zhan, Yandong Zhang, Tianhui Hu
Abstract
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.