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

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-6 π 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/EBP α /PPAR γ signaling and Perilipin signaling in vitro and in vivo. Our findings provide a promising drug model molecule for the treatment of obesity. A pair of unique caged coumarin-meroterpenoid enantiomers (+)/(−)-gerbeloid A were discovered from Gerbera piloselloides and synthesized biomimetically. (+)- 1a and (−)- 1b showed potent lipid-lowering activities in vitro and in vivo. [Display omitted] [ABSTRACT FROM AUTHOR]