Flavonoid Oxime Carbamate Derivatives: Reversal of Multidrug Resistance in Cancer Cells

The effectiveness of cancer treatment has been seriously hindered by the development of multidrug resistance (MDR), mainly mediated by efflux transporters such as P-glycoprotein (P-gp/ABCB1). Aiming at obtaining new compounds for overcoming MDR in cancer, tangeretin (1), a natural polymethoxyflavonoid, was derivatized. After obtaining the corresponding oxime (2), a set of 23 novel oxime carbamates (3-26) was prepared via carbonyldiimidazole-mediated reaction with various amines or by reaction with isocyanates. Their structures were assigned mainly by 1D and 2D NMR experiments. The compounds (1-26) were evaluated for their MDR reversal potential, using the rhodamine-123 accumulation assay and chemosensitivity experiments, in human ABCB1-gene transfected L5178Y mouse lymphoma cells. A significant increase in P-gp inhibitory activity was observed for most of the derivatives at noncytotoxic concentrations. Notably, compounds 19, 20, and 22, bearing an aliphatic substituent, were the most active, exhibiting a strong MDR reversal effect at 2 μM. Moreover, drug combination assays revealed that most of the derivatives were able to synergize doxorubicin. Selected compounds were also tested in the ATPase assay, where most of them acted as inhibitors.