Overcoming human P-glycoprotein-dependent multidrug resistance with novel dihydro-β-agarofuran sesquiterpenes

Sixteen (1–16) dihydro-β-agarofuran sesquiterpenes were isolated from the fruits of Maytenus jelskii and evaluated against mammalian cells with a multidrug resistance phenotype mediated by the overexpression of the human P-glycoprotein. Their stereostructures have been elucidated on the basis of spectroscopic analysis, including 1D and 2D NMR techniques, CD studies, chemical correlations and biogenetic means. Eight compounds from this series were discovered as potent chemosensitizers (1, 2, 4, 6, 8, 9, 11 and 14), showing similar effectiveness to or higher than the classical P-glycoprotein reversal agent verapamil, a first-generation chemosensitizer, when reversing resistance to daunomycin and vinblastine. Detailed structure–activity relationships revealed that aromatic substituents at the 6 and 9-position of the sesquiterpene scaffold were able to modulate the intensity of inhibition.

A straightforward route to new reversal agents is described: a series of dihydro-β-agarofuran sesquiterpenes, isolated from Maytenus jelskii, were able to successfully reverse human P-glycoprotein-dependent multidrug resistance. The structure–activity relationship is discussed.Figure optionsDownload as PowerPoint slideHighlights
► A series of new dihydro-β-agarofuran sesquiterpenes were isolated from Maytenus jelskii.
► Their absolute configuration was determined by CD studies.
► Sesquiterpenes as potent human MDR1/P-glycoprotein inhibitors.
► The multidrug reversal activity was strongly influence by the type of ester in the sesquiterpene scaffold.