title: Synthesis, biological evaluation, and molecular modeling of glycyrrhizin derivatives as potent high-mobility group box-1 inhibitors with anti-heart-failure activity in vivo.
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.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Du
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.forename: Jinhong
authors.initials: J
authors.lastname: Ren
authors.forename: Haining
authors.initials: H
authors.lastname: Lv
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Song
authors.initials: S
authors.lastname: Xu
authors.forename: Yadan
authors.initials: Y
authors.lastname: Wang
authors.forename: Shuanggang
authors.initials: S
authors.lastname: Ma
authors.forename: Jing
authors.initials: J
authors.lastname: Qu
authors.forename: Weibin
authors.initials: W
authors.lastname: Tang
authors.forename: Zhuowei
authors.initials: Z
authors.lastname: Hu
authors.forename: Shishan
authors.initials: S
authors.lastname: Yu
mesh_terms: D000208:Acute Disease; D000818:Animals; D002460:Cell Line; D002908:Chronic Disease; D004317:Doxorubicin; D019695:Glycyrrhizic Acid / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006333:Heart Failure / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D019695:Glycyrrhizic Acid; D004317:Doxorubicin