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

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.

Natural Berberine-Hybridized Benzimidazoles as Novel Unique Bactericides against Staphylococcus aureus

“…Natural products were significant resources of alternative classes of antibiotics with new antibacterial scaffolds . Berberine, a natural isoquinoline alkaloid isolated from several medicinal herbs such as Berberis vulgaris and Rhizoma coptidis, has been used as a nonprescription medicine to treat infectious diseases (such as bacillary dysentery, acute gastroenteritis, and cholera) in China for 2000 years. − Currently, various clinical applications of berberine have been discovered, especially in antibacterial usage, which revealed that berberine with a quaternary nitrogen, polycyclic, and planar system could helpfully increase membrane permeability and strengthen the bind affinities with amino acids in biomolecules. − Therefore, the unique and favorable structural features endowed natural berberine superiorities to be used as a novel promising scaffold for further antibacterial drug developments.…”

Merging C–H Vinylation with Switchable 6π-Electrocyclizations for Divergent Heterocycle Synthesis

“…An internal olefin could be introduced to 1a either by the current Rh-catalyzed oxidative Suzuki coupling or by Ru-catalyzed alkyne addition, delivering β-arylstyrene 103 and β-alkylstyrene 105 , which further underwent aza-eletrocyclization to generate the C6-substituted dihydropyridoisoquinolinium salts 104 and 106 (Figure a,b). As part of our continuing interest in developing anticancer agents based on PCPs, next, late-stage divergent syntheses of berberine and norchererythrine were achieved with the newly developed two-step azatricycle formation methodology as the core technology (Figure c). Specifically, Sonogashira coupling of bromide 107 and alkyne 108 afforded aldehyde 109 , which underwent Ag-mediated annulation to generate isoquinoline 110 .…”

Total Synthesis of (−)-Canadine, (−)-Rotundine, (−)-Sinactine, and (−)-Xylopinine Using a Last-Step Enantioselective Ir-Catalyzed Hydrogenation

“…The extraordinary range of biological properties displayed by these alkaloids, including (among other things) antimicrobial, anti-inflammatory, antipsychotic, and analgesic activities, have attracted significant attention although probably not as much as the capacities of some of them to act as potent and highly selective inhibitors of the a 1A -adrenoceptor, D 2 /D 1 dopamine receptor, and 5-HT 1A receptor. As such, certain tetrahydroprotoberberine alkaloids in these alkaloids have come to be regarded as important leads for the development of new antagonists for the a 1A -adrenoceptor, D 2 /D 1 dopamine receptor, and 5-HT 1A receptor …”