Flavonoid dimer as modulator of drug resistance in cancer

Multidrug resistance (MDR) is a major problem in cancer chemotherapy. The best characterized resistance mechanism is the one mediated by the overexpression of permeability-glycoprotein (P-gp) and MDR related protein 1 (MRP1), both of which can pump a variety of anticancer drugs out of the cells, resulting in lowered intracellular drug accumulation. Development of MDR modulators against P-gp and MRP1 has attracted interests from both academia and industry. Unfortunately, the first and second generation MDR modulators have failed due to various reasons including toxicity and unpredictable drug-drug interaction. We are interested in designing novel synthetic flavonoid dimers to target P-gp and MRP1 with the aim of developing specific, non-toxic and efficient MDR modulators. Some naturally-occurring flavonoids have been demonstrated to be moderate MDR modulators.To increase the specificity and affinity of flavonoids towards P-gp and MRP1, we have successfully used bivalency approach to synthesize novel flavonoid dimers and demonstrated that they are potent P-gp and MRP1 modulators in cancers.The first generation flavonoid dimer is made up of two apigenin moieties linked together by a biocompatible linker with various length of polyethylene glycol. The second generation flavonoid dimers have higher efficacy with EC50(effective concentration that reduces IC50by half ) at nM range for both P-gp and MRP1, which is comparable to that of the most potent MDR modulators available. Biochemical studies suggested that these flavonoid dimers are binding to the substrate binding site of MRP1. In summary, we have synthesized a series of novel flavonoid dimers and demonstrated that they are highly effective P-gp and MRP1 inhibitors.