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

Abstract

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.