Recent advances in the discovery of flavonoids and analogs with high‐affinity binding to P‐glycoprotein responsible for cancer cell multidrug resistance

P‐glycoprotein (P‐gp) is a plasma membrane glycoprotein that confers multidrug resistance on cells by virtue of its ability to exclude cytotoxic drugs in an ATP‐dependent manner. The most commonly considered hypothesis is that P‐gp acts as an ATP‐driven drug‐export pump, the mechanism of which is not understood in detail. Therefore, a tremendous effort is being made to find out modulator molecules to inhibit P‐gp. We have been developing flavonoid derivatives as a new class of promising modulators using a new in vitro rational‐screening assay based on measurements of the binding‐affinity toward the C‐terminal nucleotide‐binding domain (NBD2) of P‐gp. This review is focused on our results obtained with a variety of flavonoids. Structure–activity relationships of flavonoids as potential MDR modulators are reported.