A Glycyrrhizin\nDerivative with a More Potent Inhibitory\nActivity against High-Mobility Group Box 1 Efficiently Discovered\nby Chemical Synthesis Inspired by the Bioconversion Products of an\nEndophytic Fungus Isolated from Licorice

Glycyrrhizin (GL) from licorice alleviates intracerebral\nhemorrhage\n(ICH) injuries by interacting with high-mobility group box (HMGB)\n1, an inflammatory factor. We found that GL is bioconverted by endophyte\ncoexisting with licorice and succeeded in isolating two derivatives.\nThe aim of this study was to identify the compound with more potent\nHMGB1 inhibitory activity inspired by these GL derivatives. We took\nadvantage of a ketone introduced by an endophyte at the C-3 position\nand attempted methyl esterification at the C-30 position because it\nwas suggested that the water or lipid solubility of the molecule plays\nan important role. Among three derivatives synthesized, the product\nthat is both ketonized and esterified showed more potent HMGB1 inhibitory\nactivity than GL in macrophages and significantly improved adverse\nevents occurred in ICH in vivo. These results suggest that modification\nof the hydrophilicity of GL, particularly at the C-3 and C-30 positions,\nenhances the HMGB1 inhibitory activity.