Abstract |
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.
|
Authors | Dan Du, Jun Yan, Jinhong Ren, Haining Lv, Yong Li, Song Xu, Yadan Wang, Shuanggang Ma, Jing Qu, Weibin Tang, Zhuowei Hu, Shishan Yu |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 56
Issue 1
Pg. 97-108
(Jan 10 2013)
ISSN: 1520-4804 [Electronic] United States |
PMID | 23199028
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- HMGB1 Protein
- Lipopolysaccharides
- Tumor Necrosis Factor-alpha
- Glycyrrhizic Acid
- Doxorubicin
|
Topics |
- Acute Disease
- Animals
- Cell Line
- Chronic Disease
- Doxorubicin
- Glycyrrhizic Acid
(analogs & derivatives, chemistry, pharmacology)
- HMGB1 Protein
(antagonists & inhibitors, metabolism)
- Heart Failure
(chemically induced, drug therapy, physiopathology)
- Lipopolysaccharides
(pharmacology)
- Macrophages
(drug effects, metabolism)
- Mice
- Mice, Inbred C57BL
- Models, Molecular
- Molecular Docking Simulation
- Structure-Activity Relationship
- Tumor Necrosis Factor-alpha
(metabolism)
|