Synthesis, Biological Evaluation, and Molecular Modeling of Glycyrrhizin Derivatives as Potent High-Mobility Group Box‑1 Inhibitors with Anti-Heart-Failure Activity in Vivo

• Published in: Journal of medicinal chemistry 2013-01, Vol.56 (1), p.97-108
• Main Authors: Du, Dan, Yan, Jun, Ren, Jinhong, Lv, Haining, Li, Yong, Xu, Song, Wang, Yadan, Ma, Shuanggang, Qu, Jing, Tang, Weibin, Hu, Zhuowei, Yu, Shishan
• Format: Article
• Language: English
• Subjects: Acute Disease; Animals; Cell Line; Chronic Disease; Doxorubicin; Glycyrrhizic Acid - analogs & derivatives; Glycyrrhizic Acid - chemistry; Glycyrrhizic Acid - pharmacology; Heart Failure - chemically induced; Heart Failure - drug therapy; Heart Failure - physiopathology; HMGB1 Protein - antagonists & inhibitors; HMGB1 Protein - metabolism; Lipopolysaccharides - pharmacology; Macrophages - drug effects; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Models, Molecular; Molecular Docking Simulation; Structure-Activity Relationship; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm301248y

Novel glycyrrhizin (GL) derivatives were designed and synthesized by introducing various amine or amino acid residues into the carbohydrate chain and at C-30. Their inhibitory effects on high-mobility group box 1 (HMGB1) were evaluated using a cell-based lipopolysaccharide (LPS) induced tumor necrosis factor α (TNF-α) release study. Compounds 10, 12, 18–20, 23, and 24, which had substituents introduced at C-30, demonstrated moderate HMGB1 inhibition with ED50 values ranging from 337 to 141 μM, which are values comparable to that of the leading GL compound (1) (ED50 = 70 μM). Compounds 23 and 24 emerged as novel and interesting HMGB1 inhibitors. These compounds were able to extend the survival of mice with chronic heart failure (CHF) and acute heart failure (AHF), respectively. In addition, molecular modeling studies were performed to support the biological data.