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

详细信息    查看全文

• 作者：Dan Du ; Jun Yan ; Jinhong Ren ; Haining Lv ; Yong Li ; Song Xu ; Yadan Wang ; Shuanggang Ma ; Jing Qu ; Weibin Tang ; Zhuowei Hu ; Shishan Yu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：January 10, 2013
• 年：2013
• 卷：56
• 期：1
• 页码：97-108
• 全文大小：517K
• 年卷期：v.56,no.1(January 10, 2013)
• ISSN：1520-4804

文摘

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 伪 (TNF-伪) release study. Compounds 10, 12, 18鈥?b>20, 23, and 24, which had substituents introduced at C-30, demonstrated moderate HMGB1 inhibition with ED₅₀ values ranging from 337 to 141 渭M, which are values comparable to that of the leading GL compound (1) (ED₅₀ = 70 渭M). 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.