The development of multidrug resistance (MDR) often associated with overexpression of P-glycoprotein (P-gp) is a major cause of failure in cancer chemotherapy. The growing incidence of cancer and the development of MDR drive the search for novel and more effective anticancer drugs. In this context, we have recently identified Plectranthus plants as potential sources of antitumoral compounds. Moreover, we found that natural diterpenoids obtained from Plectranthus spp., namely 6,7-dehydroroyleanone (1), 7α-acetoxy-6β-hydroxyroyleanone (2) and 7α,6β-dihydroxyroyleanone (3), displayed promising cytotoxic activity.

In this work, we synthesized a small library of compounds derived from royleanones 1 and 2 and evaluated their ability to modulate P-gp activity in human non-small cell lung carcinoma NCI-H460 and its MDR counterpart NCI-H460/R. Furthermore, molecular docking and molecular dynamic studies were performed to elucidate the mechanisms by which these derivatives may exert their inhibitory P-gp activity. These studies indicate that derivatives bearing aromatic moieties exhibit increased binding affinity towards P-gp, most likely acting as non-competitive efflux modulators when bound to the M-site. Remarkably, one of these derivatives showed the ability to sensitize the resistant NCI-H460/R cells to doxorubicin, and consequently could be considered as a novel P-gp inhibitor useful in combination with classic chemotherapeutics.