Novel structure-activity relationships and selectivity profiling of cage dimeric 1,4-dihydropyridines as multidrug resistance (MDR) modulators.
Synthesized series of cage dimeric 1,4-dihydropyridines have been systematically evaluated as MDR modulators in in vitro assays to investigate structure-dependent selectivity properties of inhibiting most cancer-relevant efflux pump proteins. Structure-activity relationships of each P-glycoprotein (P-gp) and multidrug resistance associated protein (MRP) 1 and MRP2 inhibition are discussed and prove to be mainly determined by certain aromatic substitution patterns. The characterization of breast cancer resistance protein (BCRP) inhibition results in the discovery of benzyloxy substituted derivatives as selective P-gp inhibitors.
Coburger
Claudius
C
Institute of Pharmacy, Martin Luther University, 06120 Halle, Germany.
Wollmann
Jörg
J
Krug
Martin
M
Baumert
Christiane
C
Seifert
Marianne
M
Molnár
Joséf
J
Lage
Hermann
H
Hilgeroth
Andreas
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D004095:Dihydropyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D051379:Mice; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D004095:Dihydropyridines; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; C038806:1,4-dihydropyridine; C421109:multidrug resistance-associated protein 1