PPARα/γ-Targeting Amorfrutin Phytocannabinoids from Aerial Parts of Glycyrrhiza foetida

An LC-MS/MS-guided analysis of the aerial parts of Glycyrrhiza foetida afforded new phenethyl (amorfrutin)- and alkyl (cannabis)-type phytocannabinoids (six and four compounds, respectively). The structural diversity of the new amorfrutins was complemented by the isolation of six known members and the synthesis of analogues modified on the aralkyl moiety. All of the compounds so obtained were assayed for agonist activity on PPAR alpha and PPAR gamma nuclear receptors. Amorfrutin A (1) showed the highest agonist activity on PPAR gamma, amorfrutin H (7) selectively targeted PPAR alpha, and amorfrutin E (4) behaved as a dual agonist, with the pentyl analogue of amorfrutin A (11) being inactive. Decarboxyamorfrutin A (2) was cytotoxic, and modifying its phenethyl moiety to a styryl or a phenylethynyl group retained this trait, suggesting an alternative biological scenario for these compounds. The putative binding modes of amorfrutins toward PPAR alpha and PPAR gamma were obtained by a combined approach of molecular docking and molecular dynamics simulations, which provided insights on the structure-activity relationships of this class of compounds.