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

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.