Low-Cytotoxic Synthetic Bromorutaecarpine Exhibits Anti-Inflammation and Activation of Transient Receptor Potential Vanilloid Type 1 Activities

Abstract

Rutaecarpine (RUT), the major bioactive ingredient isolated from the Chinese herb Evodia rutaecarpa, possesses a wide spectrum of biological activities, including anti-inflammation and preventing cardiovascular diseases. However, its high cytotoxicity hampers pharmaceutical development. We designed and synthesized a derivative of RUT, bromo-dimethoxyrutaecarpine (Br-RUT), which showed no cytotoxicity at 20 μM. Br-RUT suppressed nitric oxide (NO) production and tumor necrosis factor-α release in concentration-dependent (0~20 μM) manners in lipopolysaccharide (LPS)-treated RAW 264.7 macrophages; protein levels of inducible NO synthase (iNOS) and cyclooxygenase-2 induced by LPS were downregulated. Br-RUT inhibited cell migration and invasion of ovarian carcinoma A2780 cells with 0~48 h of treatment. Furthermore, Br-RUT enhanced the expression of transient receptor potential vanilloid type 1 and activated endothelial NOS in human aortic endothelial cells. These results suggest that the synthetic Br-RUT possesses very low cytotoxicity but retains its activities against inflammation and vasodilation that could be beneficial for cardiovascular disease therapeutics.

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

“…Structural modifications of RUT were designed to enhance its biological activities. However, increased cytotoxicity hampers their application in vascular disorders [ 23 , 26 , 30 ]. F-RUT, a novel analog synthesized in this study with very low cytotoxicity showed anti-inflammatory activity and migration/invasion-suppressive activities that are beneficial in reducing side effects when used for pharmaceutics.…”

“…Bromo-rutaecarpine was designed to broaden the potential for application. However, the bromo-derivative is less stable than fluoro-derivatives due to it being more bulky in substitution [ 26 ]. Analogs of RUT synthesized for this study exhibited very low cytotoxicity, but had anti-inflammatory activity and TRPV1-upregulating effects.…”

Optimization of Rutaecarpine as ABCA1 Up-Regulator for Treating Atherosclerosis

“…18 Recent studies have also shown that RUT exhibits various pharmacological effects, 19,20 including cardiovascular protection, 21 antithrombotic activity, and anti-inflammatory properties. 22,23 All these effects might be beneficial in terms of reducing atherosclerosis. 24 Taken together, these data suggested that RUT might be of use in the treatment of atherosclerosis.…”