Structure-Activity Relationship Study Enables the Discovery of a Novel Berberine Analogue as RXRα Activator to Inhibit Colon Cancer
- 医学院－已发表论文 
We reported recently that berberine, a traditional oriental medicine to treat gastroenteritis, binds and activates Retinoid X receptor α (RXRα) to suppress the growth of colon cancer cells. Here, we extended our studies based on the binding mode of berberine with RXRα by design, synthesis and biological evaluation of a focused library of 15 novel berberine 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 berberine, B-12 bound and altered the conformation of RXRα/LBD, thereby suppressing Wnt/β-catenin pathway and colon cancer cell growth via RXRα mediation. In addition, B-12 not only preserved berberine’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 berberine-derived RXRα activators as novel effective antineoplastic agents for colon cancer.