Structure-Activity Relationship Study Enables The Discovery Of A Novel Berberine Analogue As The Rxr Alpha Activator To Inhibit Colon Cancer

We reported recently that berberine (Ber), a traditional oriental medicine to treat gastroenteritis, binds and activates retinoid X receptor a (RXR alpha) for suppressing the growth of colon cancer cells. Here, we extended our studies based on the binding mode of Ber with RXR alpha 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 RXR alpha activator. More efficiently than Ber, B-12 bound and altered the conformation of RXR alpha/LBD, thereby suppressing the Wnt/beta-catenin pathway and colon cancer cell growth via RXR alpha 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 RXR alpha agonists or induce hepatorenal toxicity. Together, our study describes an approach for the rational design of Ber-derived RXR alpha activators as novel effective antineoplastic agents for colon cancer.