Synthesis and Biological Evaluation of Gentiopicroside Derivatives as Novel Cyclooxygenase-2 Inhibitors with Anti-Inflammatory Activity

Abstract

Guojin Ren,1,* Qili Zhang,1,2,* Pengfei Xia,1– 4 Jie Wang,1 Pengxia Fang,1 Xiaojie Jin,1 Xuejing Peng,1– 4 Yanli Xu,1,5 Jian Zhang,1– 4 Lei Zhao1– 5 1Gansu University of Chinese Medicine, Lanzhou, 730000, People’s Republic of China; 2Northwest Collaborative Innovation Center for Traditional Chinese Medicine Co-Constructed by Gansu Province & MOE of PRC, Lanzhou, 730000, People’s Republic of China; 3Key Laboratory of Chemistry and Quality of TCM of the College of Gansu Province, Lanzhou, 730000, People’s Republic of China; 4Gansu Province Engineering Laboratory for TCM Standardization Technology and Popularization, Lanzhou, 730000, People’s Republic of China; 5Lanzhou Institute for Food and Drug Control, Lanzhou, 730000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lei Zhao; Jian Zhang, Email [email protected]; [email protected]: Nonsteroidal anti-inflammatory drugs cause a series of adverse reactions. Thus, the search for new cyclooxygenase-2 selective inhibitors have become the main direction of research on anti-inflammatory drugs. Gentiopicroside is a novel selective inhibitor of cyclooxygenase-2 from Chinese herbal medicine. However, it is highly hydrophilic owing to the presence of the sugar fragment in its structure that reduces its oral bioavailability and limits efficacy. This study aimed to design and synthesize novel cyclooxygenase-2 inhibitors by modifying gentiopicroside structure and reducing its polarity.Materials and Methods: We introduced hydrophobic acyl chloride into the gentiopicroside structure to reduce its hydrophilicity and obtained some new derivatives. Their in vitro anti-inflammatory activities were evaluated against NO, TNF-α, PGE2, and IL-6 production in the mouse macrophage cell line RAW264.7 stimulated by lipopolysaccharide. The in vivo inhibitory activities were further tested against xylene-induced mouse ear swelling. Molecular docking predicted that whether new compounds could effectively bind to target protein cyclooxygenase-2. The inhibitory activity of new compounds to cyclooxygenase-2 enzyme were verified by the in vitro experiment.Results: A total of 21 novel derivatives were synthesized, and exhibit lower polarities than the gentiopicroside. Most compounds have good in vitro anti-inflammatory activity. The in vivo activity results demonstrated that 8 compounds were more active than gentiopicroside. The inhibition rate of some compounds was higher than celecoxib. Molecular docking predicted that 6 compounds could bind to cyclooxygenase-2 and had high docking scores in accordance with their potency of the anti-inflammatory activity. The confirmatory experiment proved that these 6 compounds had significant inhibitory effect against cyclooxygenase-2 enzyme. Structure-activity relationship analysis presumed that the para-substitution with the electron-withdrawing groups may benefit the anti-inflammatory activity.Conclusion: These gentiopicroside derivatives especially PL-2, PL-7 and PL-8 may represent a novel class of cyclooxygenase-2 inhibitors and could thus be developed as new anti-inflammatory agents.Keywords: gentiopicroside derivatives, structural modification, anti-inflammatory, cyclooxygenase-2 inhibitors, molecular docking

Keywords

• gentiopicroside derivatives
• structural modification
• anti-inflammatory
• cyclooxygenase-2 inhibitors
• molecular docking