2. Academic Validation
  3. Discovery of glycosidated glycyrrhetinic acid derivatives: Natural product-based soluble epoxide hydrolase inhibitors

Discovery of glycosidated glycyrrhetinic acid derivatives: Natural product-based soluble epoxide hydrolase inhibitors

  • Eur J Med Chem. 2024 Oct 9:280:116937. doi: 10.1016/j.ejmech.2024.116937.
Qian Liu 1,  Yi-Xin Wang 1,  Zi-Hao Ge 2,  Min-Zhen Zhu 3,  Jing Ding 1,  Hao Wang 2,  Si-Meng Liu 1,  Rui-Chen Liu 1,  Chun Li 4,  Ming-Jia Yu 1,  Yue Feng 5,  Xin-Hong Zhu 6,  Jian-Hua Liang 7
Affiliations

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.
  • 4 Key Lab for Industrial Biocatalysis, Ministry of Education, Department of Chemical Engineering, Tsinghua University, Beijing, 100084, China.
  • 5 College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China. Electronic address: fengyue@mail.buct.edu.cn.
  • 6 Research Center for Brain Health, PazhouLab, Guangzhou, 510330, China. Electronic address: zhuxh527@126.com.
  • 7 Key Laboratory of Medicinal Molecule Science and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, 102488, China. Electronic address: ljhbit@bit.edu.cn.
PMID: 39413443 DOI: 10.1016/j.ejmech.2024.116937
Abstract

There are few reports on soluble Epoxide Hydrolase (sEH) structure-activity relationship studies using natural product-based scaffolds. In this study, we discovered that C-30 urea derivatives of glycyrrhetinic acid such as 33, rather than C-20/C-3 urea derivatives, possess in vitro sEH inhibitory capabilities. Furthermore, we explored the impact of stereoconfigurations at C-3 and C-18 positions, and glycosidic bonds at the 3-OH on the compound's activity. Consequently, a glycoside of 33, specifically 49Cα containing alpha-oriented mannose, exhibited promising in vivo efficacy in alleviating carrageenan-induced paw edema and acetic acid-induced writhing. Meanwhile, 49Cα demonstrated potential in mitigating acute pancreatitis by modulating the ratios of anti-inflammatory epoxyeicosatrienoic acids (EETs) to pro-inflammatory dihydroxyeicosatrienoic acids (DHETs). The co-crystal structure of sEH in complex with 49Cα revealed that the N-tetrahydropyranylmethylene urea hydrogen bonded with the residues within the sEH tunnel, contrasting with the mannose component that extended beyond the tunnel's confines. Our findings highlight 49Cα (coded LQ-38) as a promising candidate for anti-inflammatory and analgesic effects, and pave the way for the future rational design of triterpenoid-based sEH inhibitors.

Keywords

Analgesic; Anti-inflammatory; Glycyrrhetinic acid; Triterpenoid; sEH.

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