Eremane, viscidane and isozizaene diterpenoids from the leaves of Eremophila rigida and their absolute configurations

Abstract

Previously undescribed eremane, viscidane, and isozizaene diterpenoids, eremorigidanes A-F, along with six known O-methylated flavonoids and three known triterpenoids were isolated and identified from the leaves of Eremophila rigida Chinnock by combined use of high-resolution PTP1B inhibition profiling, semipreparative- and analytical-scale HPLC separations, HPLC-PDA-HRMS analysis, and NMR spectroscopy. The absolute configuration of the unreported diterpenoids were determined by comparison of their experimental and calculated ECD spectra as well as by biosynthetic arguments. All isolates were evaluated for their PTP1B inhibitory activities, which revealed the flavonoid penduletin (3) to show inhibition with an IC₅₀ value of 18.3 μM, and the triterpenoids 3,4-seco-olean-12-ene-3,28-dioic acid (15), oleanolic acid (16), and 3-oxo-oleanolic acid (17) to show inhibition with IC₅₀ values of 55.7, 9.9, and 6.3 μM, respectively. The preliminary structure-activity relationship (SAR) of isolated flavonoids and triterpenoids is discussed. Plausible biosynthetic steps involved in eremane and isozizaene metabolism are presented and discussed.

Keywords: Eremane diterpenoid; Eremophila rigida Chinnock; High-resolution inhibition profiling; Isozizaene diterpenoid; Protein tyrosine phosphatase 1B inhibitors; Scrophulariaceae; Viscidane diterpenoid.