Design, synthesis and anti-inflammatory activity of 3-amino acid derivatives of ocotillol-type sapogenins

• Published in: European journal of medicinal chemistry 2020-09, Vol.202, p.112507, Article 112507
• Main Authors: Yang, Gangqiang, Gao, Meng, Sun, Yixiao, Wang, Conghui, Fang, Xiaojuan, Gao, Hongyan, Diao, Wenshuang, Yu, Hui
• Format: Article
• Language: English
• Subjects: Anti-inflammatory activity; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Cyclooxygenase 2 - metabolism; Dose-Response Relationship, Drug; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Ginsenosides; Ginsenosides - chemical synthesis; Ginsenosides - chemistry; Ginsenosides - pharmacology; Interleukin-6 - antagonists & inhibitors; Interleukin-6 - metabolism; Lipopolysaccharides - antagonists & inhibitors; Lipopolysaccharides - pharmacology; Molecular Structure; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; NF-κB and MAPK pathways; Nitric Oxide Synthase Type II - antagonists & inhibitors; Nitric Oxide Synthase Type II - metabolism; Ocotillol-type sapogenins; Structure-Activity Relationship; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112507

Ocotillol-type sapogenins (OTS) are major ginsenoside metabolites in human hepatic tissue. In order to better utilize OTS and derivatives thereof as anti-inflammatory compounds, present study produced multiple novel 3-amino acid OTS derivatives and evaluated their anti-inflammatory activity in vitro. The nitric oxide (NO) inhibitory activity of these compounds was used for OTS structure-activity relationship (SAR) evaluations, revealing that both R/S stereochemistry at C-24 and the amino acid type at C-3 influence such NO inhibitory activity. This activity was highest for an N-Boc-protected neutral aliphatic amino acid derivative of 24R-OTS (5a), which performed better than even hydrocortisone sodium succinate in vitro. Compound 5a was also able to markedly suppress the LPS-induced upregulation of TNF-α, IL-6, iNOS, and COX-2 via the NF-κB and MAPK pathways. This suggests that OTS derivatives may be valuable anti-inflammatory compounds worthy of further preclinical evaluation. [Display omitted] •A total of 24 novel 3-amino acid derivatives of ocotillol-type sapogenins were synthesized.•Structure-activity relationships pertaining to the anti-inflammatory activity of these compounds were evaluated.•Compound 5a exhibited in vitro NO inhibitory activity superior to tested steroids.•Compound 5a suppressed inflammation, as well as NF-κB and MAPK activation.