Redesigning Berberines and Sanguinarines to Target Soluble Epoxide Hydrolase for Enhanced Anti-Inflammatory Efficacy

  • J Med Chem. 2024 Dec 26;67(24):22168-22190. doi: 10.1021/acs.jmedchem.4c02202.
Xing-Zhou Liu  1 ,  Xiao-Yu Du  2 ,  Wei-Song Xie  1 ,  Jing Ding  1 ,  Min-Zhen Zhu  3 ,  Zi-Qiang Feng  1 ,  Hao Wang  2 ,  Yue Feng  2 ,  Ming-Jia Yu  1 ,  Si-Meng Liu  1 ,  Wen-Tian Liu  1 ,  Xin-Hong Zhu  3 ,  Jian-Hua Liang  1
Affiliations
  • 1. Key Laboratory of Medicinal Molecule Science and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 102488, China.
  • 2. College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
  • 3. Research Center for Brain Health, PazhouLab, Guangzhou 510330, China.
PMID: 39658523 DOI: 10.1021/acs.jmedchem.4c02202
Abstract

Amino-berberine has remained underexplored due to limited biological evaluation and total synthesis approaches. In inflammation therapy, soluble Epoxide Hydrolase (sEH) is a promising target, yet natural scaffolds remain underutilized. Our study advances the field by redesigning natural compounds─berberine and sanguinarine─with strategic urea modifications and hydrogenated frameworks, creating novel sEH inhibitors with enhanced in vivo efficacy. Through total synthesis and structure-activity relationship studies of amino-berberine derivatives, chiral tetrahydroberberine (R)-14i (coded LXZ-42) emerged as the most potent lead, with an IC50 value of 1.20 nM. (R)-14i showed reduced CYP enzyme impact, potent therapeutic effects on acute pancreatitis, no acute in vivo toxicity, and superior pharmacokinetic properties, with an oral bioavailability of 89.3%. Structural insights from crystallography of (R)-14i bound to sEH revealed key interactions: three with the tetrahydroberberine framework and three hydrogen bonds with the urea group, highlighting (R)-14i as a novel lead for sEH-targeted therapies in inflammation.

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