Amorfrutins are an intriguing class of secondary metabolites, described for the first
time in Amorpha fruticosa, that are reported to be highly active as PPARγ (peroxisome proliferator-activated
receptor gamma) agonists. PPARγ plays a crucial role in many biological pathways involved
in type 2 diabetes mellitus and obesity, widespread pathological conditions in western
world. The available drugs active on this target are thiazolidinediones (e.g. rosiglitazone),
but their use is often associated with severe side effects. More recently, amorfrutins
have been also found in Glycyrrhiza foetida, a less investigated species of the genus Glycyrrhiza, whose phytochemical properties, despite the attractive information mentioned in
literature, have not been deepened yet ([Fig. 1]).
Fig. 1 LC-MS profile of G. foetida aerial parts extract (a). Amorfrutin A bound to PPARγ (b).
Thus, in the frame of our research activity in identifying natural compounds active
on metabolic syndrome condition, we have focused our efforts on exploring the phytochemical
space of G. foetida amorfrutins. After a preliminary LC-MS² analysis of aerial parts extract, 16 amorfrutins
were isolated through repeated chromatographic separations. Ten amorfrutins, belonging
both to the phenethyl and pentyl series, were unprecedented in literature, and were
therefore fully characterised through HRMS and 2D NMR experiments. In this communication
we will also report on the results of pharmacological tests on PPARγ and PPARα, and
on the corresponding structure-target interaction relationships. Beside the expected
activity of amorfrutin A on PPARγ, we have found a new dual activator and a selective
PPARα agonist, thus expanding the biological space of this class of natural compounds.
