2. Academic Validation
  3. A Glycyrrhizin Derivative with a More Potent Inhibitory Activity against High-Mobility Group Box 1 Efficiently Discovered by Chemical Synthesis Inspired by the Bioconversion Products of an Endophytic Fungus Isolated from Licorice

A Glycyrrhizin Derivative with a More Potent Inhibitory Activity against High-Mobility Group Box 1 Efficiently Discovered by Chemical Synthesis Inspired by the Bioconversion Products of an Endophytic Fungus Isolated from Licorice

  • J Med Chem. 2024 Sep 26;67(18):16328-16337. doi: 10.1021/acs.jmedchem.4c01213.
Aoi Machida 1,  Kengo Banshoya 1 2,  Akiho Miyamaru 2,  Tamaki Eto 2,  Shoji Maehara 3,  Yuhzo Hieda 4,  Toshiyuki Hata 3,  Masatoshi Ohnishi 1 2
Affiliations

Affiliations

  • 1 Department of Pharmacotherapeutics, Graduate School of Pharmacy and Pharmaceutical Sciences, Fukuyama University, 985-1, Sanzo, Higashimura-cho, Fukuyama, Hiroshima 729-0292, Japan.
  • 2 Department of Pharmacotherapeutics, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, 985-1, Sanzo, Higashimura-cho, Fukuyama, Hiroshima 729-0292, Japan.
  • 3 Department of Physical Chemistry for Bioactive Molecules, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, 985-1, Sanzo, Higashimura-cho, Fukuyama, Hiroshima 729-0292, Japan.
  • 4 Common Resources Center, Fukuyama University, 985-1, Sanzo, Higashimura-cho, Fukuyama, Hiroshima 729-0292, Japan.
PMID: 39231005 DOI: 10.1021/acs.jmedchem.4c01213
Abstract

Glycyrrhizin (GL) from licorice alleviates intracerebral hemorrhage (ICH) injuries by interacting with high-mobility group box (HMGB) 1, an inflammatory factor. We found that GL is bioconverted by endophyte coexisting with licorice and succeeded in isolating two derivatives. The aim of this study was to identify the compound with more potent HMGB1 inhibitory activity inspired by these GL derivatives. We took advantage of a ketone introduced by an endophyte at the C-3 position and attempted methyl esterification at the C-30 position because it was suggested that the water or lipid solubility of the molecule plays an important role. Among three derivatives synthesized, the product that is both ketonized and esterified showed more potent HMGB1 inhibitory activity than GL in macrophages and significantly improved adverse events occurred in ICH in vivo. These results suggest that modification of the hydrophilicity of GL, particularly at the C-3 and C-30 positions, enhances the HMGB1 inhibitory activity.

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