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

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

  • J Med Chem. 2020 Jun 11;63(11):5841-5855. doi: 10.1021/acs.jmedchem.0c00088.
Beibei Xu 1 Xunjin Jiang 2 Jing Xiong 1 Jun Lan 3 Yuan Tian 1 Linhai Zhong 1 Xinquan Wang 3 Ning Xu 3 Hanwei Cao 1 Wenqing Zhang 1 Hao Zhang 4 Xiaoting Hong 1 Yan-Yan Zhan 1 Yandong Zhang 2 Tianhui Hu 1
Affiliations

Affiliations

  • 1 Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361005, China.
  • 2 Department of Chemistry and Key Laboratory of Chemical Biology of Fujian Province, iChEM, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, China.
  • 3 Department of Biological Sciences, Tsinghua University, Beijing 100084, China.
  • 4 Institute of Precision Cancer Medicine and Pathology, Jinan University Medical College, Guangzhou 510632, China.
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.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-133739
    RAR/RXR抑制剂