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.
Boumendjel
Ahcène
A
Département de Pharmacochimie Moléculaire, UMR-CNRS 5063, UFR de Pharmacie de Grenoble, 38706 La Tronche, France. ahcene.boumendjel@ujf-grenoble.fr
Di Pietro
Attilio
A
Dumontet
Charles
C
Barron
Denis
D
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005419:Flavonoids / Q000737:chemistry / Q000378:metabolism*; D015394:Molecular Structure; D011485:Protein Binding; D013329:Structure-Activity Relationship
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005419:Flavonoids