(+)/(-)-Gerbeloid A,a pair of unprecedented coumarin-based polycyclic meroterpenoid enantiomers from Gerbera piloselloides:Structural elucidation,semi-synthesis,and lipid-lowering activity  

作　　者：Chenxu Zhao Jingrong Li Yue Hu Lingyu Li Meng Yu Yunfeng Huang Tao Zhang Hai Shang Zhongmei Zou 

机构地区：[1]State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Institute of Medicinal Plant Development,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100193,China [2]Institute of Chinese Medicine Resources,Guangxi Institute of Chinese Medicine&Pharmaceutical Science,Nanning 530000,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第6期2657-2668,共12页药学学报（英文版）

基　　金：support from the Natural Sciences Foundation of China(82374035);the CAMS Innovation Fund for Medical Sciences(CIFMS,2022-I2M-1-017,China).

摘　　要：A pair of coumarin-based polycyclic meroterpenoid enantiomers(+)/(-)-gerbeloid A[(+)-1a and(-)-1b]were isolated from the medicinal plant Gerbera piloselloides,which have a unique caged oxatricyclo[4.2.2.0^(3,8)]decene scaffold.Their planar and three-dimensional structures were exhaustively characterized by comprehensive spectroscopic data and X-ray diffraction analysis.Guided by the hypothetical biosynthetic pathway,the biomimetic synthesis of racemic 1 was achieved using 4-hydroxy-5-methylcoumarin and citral as the starting material via oxa-6πelectrocyclization and intramolecular[2+2]photocycloaddition.Subsequently,the results of the biological activity assay demonstrated that both(+)-1a and(-)-1b exhibited potent lipid-lowering effects in 3T3-L1 adipocytes and the high-fat diet zebrafish model.Notably,the lipid-lowering activity of(+)-1a is better than that of(-)-1b at the same concentration,and molecular mechanism study has shown that(+)-1a and(-)-1b impairs adipocyte differentiation and stimulate lipolysis by regulating C/EBPα/PPARγsignaling and Perilipin signaling in vitro and in vivo.Our findings provide a promising drug model molecule for the treatment of obesity.

关 键 词：Gerbera piloselloides Natural products Coumarin meroterpenoid Structural elucidation Biomimetic synthesis Lipid-lowering activity 3T3-L1 adipocytes High-fat diet zebrafish model 

分 类 号：R914[医药卫生—药物化学]