Structure-activity relationships for euphocharacins A-L, a new series of jatrophane diterpenes, as inhibitors of cancer cell P-glycoprotein

The Mediterranean spurge Euphorbia characias L. afforded twelve new diterpenes based on a jatrophane skeleton named euphocharacins A - L. Their chemical structures were elucidated by extensive nuclear magnetic resonance and mass spectrometry methods. Euphocharacins A-L were tested as inhibitors of the daunomycin-efflux activity of P-glycoprotein from cancer cells. The results were used to extend the structure-activity relationship established for this class of compounds, highlighting the positive effects of propyl and benzoyl groups at positions 3 and 9, respectively, and evidencing the negative effect of a free hydroxyl group at position 2. Among the tested compounds, euphocharacins C and I showed an activity higher than cyclosporin to inhibit Pgp-mediated daunomycin transport.