Flavonoids from Ericameria nauseosa inhibiting PI3K/AKT pathway in human melanoma cells

The PI3K/AKT and MAPK/ERK pathways are frequently mutated in metastatic melanoma. In a screen of over 2500 plant extracts, the dichloromethane extract of Ericameria nauseosa significantly inhibited oncogenic activity of AKT in MM121224 human melanoma cells. This extract was analyzed by analytical HPLC, and the column effluent was fractionated and tested for activity to generate the so-called HPLC-based activity profile. Compounds eluting within active time-windows of the chromatogram were subsequently isolated in a larger scale to afford 11 flavones (1-11), four flavanones (12-15), two diterpenes (16, 17), and a seco-caryophyllene (18). All isolated compounds were tested for activity, whereby only flavonoids were found active. Of these, flavones were shown to be more active than the flavanones. The most potent flavone was compound 9, that was displaying an IC50 of 14.7 +/- 1.4 mu M on AKT activity in MM121224 cells. The terpenoids (16-18) were found to be inactive in the assay. Both diterpenes, a grindelic acid derivative (16) and an ent-neo-clerodane (17) were identified as new natural products. Their absolute configuration was established by ECD. Compound 17 is the first description of a clerodane type diterpene in the genus Ericameria.

Automated summary

The PI3K/AKT and MAPK/ERK pathways are frequently mutated in metastatic melanoma. In this study, a plant extract from Ericameria nauseosa was found to inhibit the oncogenic activity of AKT in human melanoma cells. Further analysis led to the identification of several active compounds, including flavones, which were more potent than flavanones. Two new natural products, diterpenes, were also discovered in this extract.