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
  • 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.
PMID: 32391701 DOI: 10.1021/acs.jmedchem.0c00088
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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