New amorfrutins from Glycyrrhiza foetida and their profile of PPARγ/α modulation

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.

 

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Publication History

Article published online:
16 November 2023