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

Abstract

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.

Fluorine-Modified Rutaecarpine Exerts Cyclooxygenase-2 Inhibition and Anti-inflammatory Effects in Lungs

“…In our previous study, we established the anti-inflammatory function of F-RUT in macrophages (Lee et al, 2017). The stimulation of epithelial cells by inflammatory stimuli plays a critical role during the progression of lung fibrosis.…”

“…Owing to this, the anti-inflammatory activity of RUT was previously explored (Chiou et al, 1992, 1997). F-RUT, the newly synthesized derivative of RUT, was previously shown to possess anti-inflammatory activity and exhibit lower cytotoxicity, spurring its pharmaceutical development (Lee et al, 2017). The present study explored the additional effects of F-RUT on respiratory function as well as morphological changes using a mice model.…”

“…Potential applications of fluorine were also found in agrochemical, pharmaceutical, and material development (Yuan et al, 2017). Several fluorinated RUT compounds have been synthesized, but only F-RUT exhibited good anti-inflammatory activity (Lee et al, 2017). Results from a molecular docking simulation also proposed a mechanism used by F-RUT to exhibit its COX-2-inhibitory activity, and provided a fluorination position of molecular reference for pharmacokinetic purposes.…”

“…Fluoro-2-methoxyrutaecarpine (F-RUT) was synthesized as previously reported (Lee et al, 2017). In brief, 2-amino-4,5-dimethoxybenzoic acid (0.24 g, 1.5 mmol) was dissolved in toluene (5 mL, 0°C) and added dropwise to thionyl chloride (0.87 mL, 7.4 mmol).…”

“…Recent studies have demonstrated that RUT can suppress cell migration and COX-2 activity (Moon et al, 1999; Chiou et al, 2011). In our previous work, we synthesized the RUT derivative, fluoro-2-methoxyrutaecarpine (F-RUT), and demonstrated its anti-inflammatory effect in macrophages (Lee et al, 2017). In this study, we further explored its therapeutic effect in the reduction of inflammatory damage in lungs.…”