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

Abstract

We reported recently that <b>berberine</b> (<b>Ber</b>), 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 <b>Ber</b> with RXRα by design, synthesis, and biological evaluation of a focused library of 15 novel <b>Ber</b> analogues. Among them, 3,9-dimethoxy-5,6-dihydroisoquinolino[3,2-<i>a</i>]isoquinolin-7-ium chloride (<b>B-12</b>) was identified as the optimal RXRα activator. More efficiently than <b>Ber</b>, <b>B-12</b> 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>B-12</b> not only preserved <b>Ber</b>'s tumor selectivity but also greatly improved its bioavailability. Remarkably, in mice, <b>B-12</b> 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 <b>Ber</b>-derived RXRα activators as novel effective antineoplastic agents for colon cancer.