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

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

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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[4.2.2.03,8]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-6π electrocyclization 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/PPARγ signaling and Perilipin signaling in vitro and in vivo.Our findings provide a promising drug model molecule for the treatment of obesity.

Gerbera piloselloidesNatural productsCoumarin meroterpenoidStructural elucidationBiomimetic synthesisLipid-lowering activity3T3-L1 adipocytesHigh-fat diet zebrafish model

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

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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

Institute of Chinese Medicine Resources,Guangxi Institute of Chinese Medicine & Pharmaceutical Science,Nanning 530000,China

Natural Sciences Foundation of ChinaCAMS Innovation Fund for Medical Sciences,ChinaCAMS Innovation Fund for Medical Sciences,China

82374035CIFMS2022-I2M-1-017

2024

10.1016/j.apsb.2024.03.035

药学学报(英文版)

药学学报(英文版)

CSTPCD
ISSN：
年,卷(期)：2024.14(6)
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