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In a cross-continental research initiative, including researchers working in Australia and Denmark, and based on joint external funding by a 3-year grant from the Novo Nordisk Foundation, we have used DNA sequencing, extensive chemical profiling and molecular networking analyses across the entire Eremophila genus to provide new knowledge on the presence of natural products and their bioactivities using polypharmocological screens. Sesquiterpenoids, diterpenoids and dimers of branched-chain fatty acids with previously unknown chemical structures were identified. The collection of plant material from the Eremophila genus was carried out according to a 'bioprospecting agreement' with the Government of Western Australia. We recognize that several Eremophila species hold immense cultural significance to Australia's First Peoples. In spite of our best intentions to ensure that new knowledge gained about the genus Eremophila and any potential future benefits are shared in an equitable manner, in accordance with the Nagoya Protocol, we encounter serious dilemmas and potential conflicts in making benefit sharing with Australia's First Peoples a reality. Refereed/Peer-reviewed

Multidrug resistance (MDR) is a major challenge in cancer treatment, and the breast cancer resistance protein (BCRP) is an important target in the search for new MDR-reversing drugs. With the aim of discovering new potential BCRP inhibitors, the crude extract of leaves of Eremophila galeata, a plant endemic to Australia, was investigated for inhibitory activity of parental (HT29par) as well as BCRP-overexpressing HT29 colon cancer cells resistant to the chemotherapeutic SN-38 (i.e., HT29SN38 cells). This identified a fraction, eluted with 40% acetonitrile on a solid-phase extraction column, which showed weak growth-inhibitory activity on HT29SN38 cells when administered alone, but exhibited concentration-dependent growth inhibition when administered in combination with SN-38. The major constituent in this fraction was isolated and found to be 5,3′,5′-trihydroxy-3,6,7,4′-tetramethoxyflavone (2), which at a concentration of 25 μg/mL potentiated the growth-inhibitory activity of SN-38 to a degree comparable to that of the known BCRP inhibitor Ko143 at 1 μM. A dye accumulation experiment suggested that 2 inhibits BCRP, and docking studies showed that 2 binds to the same BCRP site as SN-38. These results indicate that 2 acts synergistically with SN-38, with 2 being a BCRP efflux pump inhibitor while SN-38 inhibits topoisomerase-1.

Eremophila (Scrophulariaceae) is a genus of Australian desert plants, which have been used by Australian Aboriginal people for various medicinal purposes. Crude extracts of the leaf resin of Eremophila glabra (R.Br.) Ostenf. showed α-glucosidase and protein tyrosine phosphatase 1B (PTP1B) inhibitory activity with IC50 values of 19.3 ± 1.2 μg/mL and 11.8 ± 2.1 μg/mL, respectively. Dual α-glucosidase/PTP1B high-resolution inhibition profiling combined with HPLC-PDA-HRMS and NMR were used to isolate and identify the compounds providing these activities. This resulted in isolation of seven undescribed serrulatane diterpenoids, eremoglabrane A-G, together with nine previously identified serrulatane diterpenoids and flavonoids. Three of the serrulatane diterpenoids showed PTP1B inhibitory activities with IC50 values from 63.8 ± 5.8 μM to 104.5 ± 25.9 μM.