Multidrug resistance (MDR) is one of the major obstacles in cancer chemotherapy. MDR is often associated with overexpression of the efflux pump, P-glycoprotein (P-gp). 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 recognized Plectranthus plants as potential sources of lead compounds. Accordingly, two natural diterpenoids, 6,7-dehydroroyleanone (1) and 7α-acetoxy-6β-hydroxyroyleanone (2) obtained from Plectranthus spp., exhibited promising cytotoxic activity.

In this work, the reactivity of 1 and 2 was studied to synthesize a library of new derivatives with P-gp inhibitory potential. The ability to inhibit P-gp activity was evaluated in human non-small cell lung carcinoma NCI-H460 and its MDR counterpart NCI-H460/R. Furthermore, molecular docking and molecular dynamics studies were conducted to explain the molecular interaction of royleanones with P-gp.

Royleanones 1 and 2 showed similar cytotoxic activity against cancer cell lines and MDR cancer cell lines. Two benzoylated derivatives displayed improved P-gp inhibition activity comparing to the natural ones (1 and 2). Interestingly, one of these derivatives also displayed the ability to sensitize the resistant NCI-H460/R cells to doxorubicin and therefore could be considered as a novel P-gp inhibitor suitable in combination with classic anticancer drugs.