Peptidomimetic glutathione analogues as novel gammaGT stable GST inhibitors.
Elevated levels of glutathione-S-transferase (GST) isoenzymes are found in many tumor cells and are thought to play a role in the onset of multidrug resistance (MDR). To evaluate the contribution of GST to this process, inhibitors are needed. Glutathione (GSH) conjugates, although good GST inhibitors, cannot be used in vivo, because they are eliminated rapidly. In this paper, we describe the synthesis of a series of novel peptidomimetic glutathione analogues that are stabilized against peptidase mediated breakdown. The peptide bonds in GSH were replaced by isosteres, such as the 'reduced' amide (which was prepared using a novel method), N-methylamide, urethane, and methylene linkages. The in vitro evaluation of the compounds focuses on GST inhibition and stability towards gamma-glutamyl-transpeptidase (gammaGT), the main enzyme involved in GSH breakdown. The compounds were conjugated to the model electrophile ethacrynic acid (EA) to resemble GS-EA, an efficient GST inhibitor. All novel GSH-analogues were shown to inhibit rat liver cytosolic GSTs. Furthermore, peptidomimetic changes of the gamma-glutamyl-cysteine amide bond greatly improved stability towards gammaGT. These compounds may therefore be useful in the design of novel in vivo applicable GST inhibitors.
Burg
Danny
D
Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, PO Box 9503, 2300RA, Leiden, The Netherlands. d.burg@lacdr.leidenuniv.nl
Filippov
Dmitri V
DV
Hermanns
Ralph
R
van der Marel
Gijs A
GA
van Boom
Jacques H
JH
Mulder
Gerard J
GJ
D000818:Animals; D003600:Cytosol / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005978:Glutathione / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D018716:Molecular Mimicry; D051381:Rats; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D004791:Enzyme Inhibitors; D005723:gamma-Glutamyltransferase; D005982:Glutathione Transferase; D005978:Glutathione