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. Copyright 2002 Wiley Periodicals, Inc. Med Res Rev, 22, No. 5, 512-529, 2002; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/med.10015