Inhibition of the multidrug resistance protein 1 (MRP1) by peptidomimetic glutathione-conjugate analogs.
Inhibition of multidrug resistance protein 1 (MRP1) mediated cytostatic drug efflux might be useful in the treatment of drug resistant tumors. Because the glutathione (GSH) conjugate of ethacrynic acid (EA), GS-EA, is a good substrate of MRP1, GS-EA derivatives are expected to be good inhibitors of MRP1. To study structure-activity relationships of MRP1 inhibition, a series of novel GS-EA analogs was synthesized in which peptide bonds of the GSH backbone were replaced by isosteric groups [Bioorg Med Chem 10:195-205, 2002]. Several of these compounds were effective inhibitors of MRP1-mediated [(3)H]GS-EA and [(3)H]E(2)17betaG transport, as studied in membrane vesicles prepared from MRP1-overproducing Sf9 cells. The modifications of the peptide backbone have distinct implications for recognition by MRP1: the gamma-glutamyl-cysteine peptide bond is important for binding, whereas the cysteinyl-glycine amide does not seem essential. When the gamma-glutamyl-cysteine peptide bond (C-CO-N) is replaced by a urethane isostere (O-CO-N), an effective competitive MRP1-inhibitor (K(i) = 11 microM) is obtained. After esterification of this compound to improve its cellular uptake, it inhibited MRP1-mediated efflux of calcein from 2008 ovarian carcinoma cells overexpressing MRP1. This compound also partially reversed the resistance of these cells to methotrexate. Because the urethane isostere is stable toward gamma-glutamyl transpeptidase-mediated breakdown, it is an interesting lead-compound for the development of in vivo active MRP1 inhibitors.
Burg
Danny
D
Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
Wielinga
Peter
P
Zelcer
Noam
N
Saeki
Tohru
T
Mulder
Gerard J
GJ
Borst
Piet
P
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004958:Estradiol / Q000493:pharmacokinetics; D005452:Fluoresceins / Q000493:pharmacokinetics; D020719:Glucuronides / Q000378:metabolism; D005978:Glutathione / Q000737:chemistry / Q000494:pharmacology*; D007313:Insecta / Q000166:cytology; D007700:Kinetics; D008727:Methotrexate / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D014316:Tritium
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005452:Fluoresceins; D020719:Glucuronides; D010455:Peptides; D014316:Tritium; D004958:Estradiol; D005978:Glutathione; C007740:fluorexon; D008727:Methotrexate