Synthesis, in vitro and in vivo biological evaluation of novel lappaconitine derivatives as potential anti-inflammatory agents  

作　　者：Lei Pang Chun-Yan Liu Guo-Hua Gong Zhe-Shan Quan 

机构地区：[1]Key Laboratory of Natural Resources and Functional Molecules of the Changbai Mountain,Affiliated Ministry of Education,College of Pharmacy,Yanbian University,Yanji 133002,China [2]Affiliated Hospital of Inner Mongolia University for Nationalities,Tongliao 028000,China

出　　处：《Acta Pharmaceutica Sinica B》2020年第4期628-645,共18页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(No.21662036).

摘　　要：Lappaconitine(LA),a natural compound with a novel C18-diterpenoid alkaloid skeleton,displayed extensive biological profile.Recent research on LA is focused mainly on its anti-tumor and analgesic effects,and therefore we aimed to investigate its anti-inflammatory potential.A series of novel LA derivatives with various substituents on the 20-N position was designed and synthesized.In the initial screening of LA derivatives against NO production,all the target compounds,except compound E2,exhibited excellent inhibitory ability relative to that of LA.Particularly,compound A4 exhibited the most potent inhibition with IC50 of 12.91 mmol/L.The elementary structureeactivity relationships(SARs)of NO inhibitory activity indicated that replacement of the benzene ring with an electron donating group could improve the anti-inflammatory efficacy.Furthermore,compound A4 shows an anti-inflammatory mechanism by inhibiting NO,PGE2,and TNF-a generation via the suppression of NF-kB and MAPK signaling pathways.Notably,compound A4 could exert a significant therapeutic effect on LPS-induced acute lung injury(ALI)in vivo.Based on the above research,we further investigated the preliminary pharmacokinetic property of A4 in rats.Therefore,compound A4 could be a promising candidate for the development of anti-inflammatory agents in the future.

关 键 词：LAPPACONITINE ANTI-INFLAMMATORY activity NF-KB MAPK Acute LUNG injury PHARMACOKINETIC study 

分 类 号：R914[医药卫生—药物化学] R96[医药卫生—药学]