Quercetin–POM (pivaloxymethyl) conjugates: Modulatory activity for P-glycoprotein-based multidrug resistance

BackgroundWe previously demonstrated that the bioactivity of quercetin could be improved through conjugation with a hydrolysable pivaloxymethyl (POM) group.PurposePresent study aimed to evaluate MDR (multidrug resistance)-modulatory activity of the quercetin–POM conjugates.Study design/methodsMDR-modulatory activity was determined by measuring cytotoxicity of various anticancer agents to MDR MES-SA/Dx5 cell lines upon combination with the quercetin–POM conjugates.ResultsThe quercetin–7-O-POM conjugate (7-O-POM-Q) was significantly more potent than quercetin in reversing MDR, which recovered the cytotoxicity of various anticancer agents with EC50 values of 1.1–1.3 µM. A series of mechanistic studies revealed that 7-O-POM-Q competes with verapamil in binding to the same drug-binding site of the major MDR target, Pgp (P-glycoprotein), and inhibits Pgp-mediated drug efflux with a similar potency as verapamil. The physicochemical properties of 7-O-POM-Q were then evaluated, which confirmed that 7-O-POM-Q has remarkably enhanced cellular uptake and intracellular localization compared with quercetin. Additionally, it is noteworthy that 7-O-POM-Q undergoes slow hydrolysis to quercetin over a prolonged period of time.ConclusionThe quercetin–POM conjugate showed significantly improved MDR-reversing activity compared with quercetin, which could be attributed to its capacity to maintain high intracellular concentrations.

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