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,Journal of Medicinal Chemistry

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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
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-04 , 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}

Affiliation

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.

中文翻译：

一种对高迁移率组具有更强抑制活性的甘草甜素衍生物框 1 通过化学合成有效发现，其灵感来自从甘草中分离的内生真菌的生物转化产物

甘草中的甘草甜素（GL）通过与炎症因子高迁移率族箱（HMGB） 1 相互作用来减轻脑出血（ICH）损伤。我们发现 GL 通过与甘草共存的内生菌进行生物转化，并成功分离了两种衍生物。本研究的目的是确定受这些 GL 衍生物启发的具有更强 HMGB1 抑制活性的化合物。我们利用内生菌在 C-3 位引入的酮，并尝试在 C-30 位点进行甲酯化，因为有人认为分子的水溶性或脂溶性起着重要作用。在合成的 3 种衍生物中，酮化和酯化产物在巨噬细胞中显示出比 GL 更有效的 HMGB1 抑制活性，并显着改善了 ICH 体内发生的不良事件。这些结果表明，GL 亲水性的修饰，特别是在 C-3 和 C-30 位置，增强了 HMGB1 的抑制活性。

更新日期：2024-09-04

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