Synthetic Fluororutaecarpine Inhibits Inflammatory Stimuli and Activates Endothelial Transient Receptor Potential Vanilloid-Type 1

• Published in: Molecules (Basel, Switzerland) Vol. 22; no. 4; p. 656
• Main Authors: Lee, Chi-Ming, Gu, Jiun-An, Rau, Tin-Gan, Wang, Chi, Yen, Chiao-Han, Huang, Shih-Hao, Lin, Feng-Yen, Lin, Chun-Mao, Huang, Sheng-Tung
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 19.04.2017; MDPI
• Subjects: Alum; Aluminum sulfate; Animals; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - pharmacology; Anticoagulants; Aorta; Capsaicin receptors; Cell Movement - drug effects; Cyclooxygenase 2 - metabolism; Cyclooxygenase-2; Cytotoxicity; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Herbal medicine; Humans; Indole Alkaloids - chemical synthesis; Indole Alkaloids - pharmacology; Inflammation; Lead compounds; Lipopolysaccharides; Lipopolysaccharides - immunology; Macrophages; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Mice; Natural products; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - metabolism; Nitric Oxide Synthase Type III - metabolism; Nitric-oxide synthase; Ovalbumin; Quinazolines - chemical synthesis; Quinazolines - pharmacology; Therapeutic applications; Transient receptor potential proteins; TRPV Cation Channels - agonists; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Vasodilation; fluoro-rutaecarpine; TRPV-1; iNOS; eNOS; inflammation
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules22040656

The natural product, rutaecarpine (RUT), is the main effective component of Evodia rutaecarpa which is a widely used traditional Chinese medicine. It has vasodilation, anticoagulation, and anti-inflammatory activities. However, further therapeutic applications are limited by its cytotoxicity. Thus, a derivative of RUT, 10-fluoro-2-methoxyrutaecarpine (F-RUT), was designed and synthesized that showed no cytotoxicity toward RAW264.7 macrophages at 20 μM. In an anti-inflammation experiment, it inhibited the production of nitric oxide (NO) and tumor necrosis factor (TNF)-α in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages; cyclooxygenase (COX)-2 and inducible NO synthase (iNOS) induced by LPS were also downregulated. After 24 h of treatment, F-RUT significantly inhibited cell migration and invasion of ovarian A2780 cells. Furthermore, F-RUT promoted expressions of transient receptor potential vanilloid type 1 (TRPV1) and endothelial (e)NOS in human aortic endothelial cells, and predominantly reduced the inflammation in ovalbumin/alum-challenged mice. These results suggest that the novel synthetic F-RUT exerts activities against inflammation and vasodilation, while displaying less toxicity than its lead compound.