Nonprenylated rotenoids, a new class of potent breast cancer resistance protein inhibitors.
Two rotenoids isolated from Boerhaavia diffusa (Nyctaginaceae), boeravinones G (1) and H (2), have been found to potently inhibit the drug efflux activity of breast cancer resistance protein (BCRP/ABCG2), a multidrug transporter responsible for cancer cell resistance to chemotherapy. The isolation of nine additional rotenoid derivatives (3-11), including the new boeravinones I (10) and J (11), from the extract of B. diffusa roots allowed us to establish structure-activity relationships toward inhibition of BCRP-mediated drug transport activity. The results show the positive roles of a methoxy group at position 6 of ring B and the absence of a substituent at position 10, and the requirement for a 6a/12a double bond between rings B and C. In contrast, both contraction of ring B, to give a coumaronochromone (11), and tetrasubstitution of ring D appeared to be detrimental for the inhibitory potency. The present study provides the first data on the BCRP-inhibiting activity of rotenoid derivatives, indicating boeravinones as a new class of interesting BCRP inhibitors.
Ahmed-Belkacem
Abdelhakim
A
Institut de Biologie et Chimie des Protéines, UMR 5086 CNRS/Université Lyon 1, IFR 128 BioSciences Gerland Lyon-Sud, 7 Passage du Vercors, 69367 Lyon, France.
Macalou
Sira
S
Borrelli
Francesca
F
Capasso
Raffaele
R
Fattorusso
Ernesto
E
Taglialatela-Scafati
Orazio
O
Di Pietro
Attilio
A
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D002460:Cell Line; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007529:Isoflavones / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D039281:Nyctaginaceae / Q000737:chemistry*; D010936:Plant Extracts / Q000737:chemistry / Q000302:isolation & purification; D013329:Structure-Activity Relationship
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D007529:Isoflavones; D009363:Neoplasm Proteins; D010936:Plant Extracts