文献类型：期刊文献

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

作者：Ren, Guojin[1];Zhang, Qili[1,2];Xia, Pengfei[1,2,3,4];Wang, Jie[1];Fang, Pengxia[1];Jin, Xiaojie[1];Peng, Xuejing[1,2,3,4];Xu, Yanli[1,5];Zhang, Jian[1,2,3,4];Zhao, Lei[1,2,3,4,5]

第一作者：Ren, Guojin

通信作者：Zhang, J[1];Zhao, L[1];Zhang, J[2];Zhao, L[2];Zhang, J[3];Zhao, L[3];Zhang, J[4];Zhao, L[4];Zhao, L[5]

机构：[1]Gansu Univ Chinese Med, Lanzhou 730000, Peoples R China;[2]Northwest Collaborat Innovat Ctr Tradit Chinese Me, Lanzhou 730000, Peoples R China;[3]Qual TCM Coll Gansu Prov, Key Lab Chem, Lanzhou 730000, Peoples R China;[4]Gansu Prov Engn Lab TCM Standardizat Technol & Pop, Lanzhou 730000, Peoples R China;[5]Lanzhou Inst Food & Drug Control, Lanzhou 730000, Peoples R China

第一机构：甘肃中医药大学

通信机构：[1]corresponding author), Gansu Univ Chinese Med, Lanzhou 730000, Peoples R China;[2]corresponding author), Northwest Collaborat Innovat Ctr Tradit Chinese Me, Lanzhou 730000, Peoples R China;[3]corresponding author), Qual TCM Coll Gansu Prov, Key Lab Chem, Lanzhou 730000, Peoples R China;[4]corresponding author), Gansu Prov Engn Lab TCM Standardizat Technol & Pop, Lanzhou 730000, Peoples R China;[5]corresponding author), Lanzhou Inst Food & Drug Control, Lanzhou 730000, Peoples R China.|[10735]甘肃中医药大学;

年份：2023

卷号：17

起止页码：919

外文期刊名：DRUG DESIGN DEVELOPMENT AND THERAPY

收录：;Scopus(收录号：2-s2.0-85151188803);WOS:【SCI-EXPANDED(收录号:WOS:000971348600001)】；

基金：Acknowledgments This work was supported by the National Natural Science Foundation of China (no. 82160457, no. 81660577) and the Natural Science Foundation of Gansu Province (no. 21JR7RA564) . We sincerely thank Dr. Jun Zeng of Lanzhou University for helping us with the chemistry experiments.

语种：英文

外文关键词：gentiopicroside derivatives; structural modification; anti-inflammatory; cyclooxygenase-2 inhibitors; molecular docking

摘要：Purpose: 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-alpha, 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.