Modified Jatrophane Diterpenes as Modulators of Multidrug Resistance from Euphorbia dendroides L

Four new C22 diterpenoids with a 17-ethyljatrophane skeleton, named terracinolides J-L (1-3) and 13-OH terracinolide F (8) have been identified from the latex of Euphorbia dendroides L., together with the known terracinolides B, C, F and H (4-7) and 13-OH terracinolides B and G (9 and 10) previously found in Euphorbia terracina L. and Euphorbia segetalis L. Two further new compounds, named abeodendroidin F (11) and epiabeodendroidin F (12), possessing a six-membered A ring, have been isolated. Remarkably, only epiabeodendroidin F (12) could be obtained from the jatrophane euphodendroidin F (13) by neutral alumina-promoted -ketol rearrangement. The stereostructures of new compounds have been determined on the basis of spectral analysis, including HR-FABMS, HSQC, HMBC and ROESY experiments. The new compounds and six co-occurring known terracinolides were tested as inhibitors of the drug-efflux activity of P-glycoprotein from cancer cells. The results were used to extend the structure-activity relationships established for this class of compounds highlighting the relevance of substitution at positions 3, 6 and 15, and disclosing a remarkable tolerance toward connectivity changes in the terpenoid core.