Synthesis and activity of the glutathione analogue gamma-(L-gamma-azaglutamyl)-L-cysteinyl-glycine.
The backbone-modified glutathione analogue gamma-(L-gamma-azaglutamyl)-L-cysteinyl-glycine 7, characterized by the presence of a NHCONH urea linkage deriving from the replacement of the native Glu gamma-CH2 with the aza (NH) group, was synthesized and fully characterized by FAB-MS, 1H- and 13C-NMR. Potential of 7 and its oxidized form 6 as gamma-glutamyltransferase inhibitors was investigated. Both compounds 7 and 6 were found to be competitive inhibitors of hog kidney gamma-glutamyltransferase (EC 2.3.2.2.) by binding at the donor site: the reduced analogue is a more efficient inhibitor than glutathione of the gamma-glutamyl transfer reaction. Inhibition at the acceptor site, which is also present, appears to be more complex. In particular, un-competitive inhibition is observed for compound 7. The results indicate that gamma-azapeptides of type 7 may represent interesting targets in the search for stable inhibitors of gamma-glutamyltransferases.
Calcagni
A
A
Department of Pharmaceutical Studies, La Sapienza University, Rome, Italy.
Dupré
S
S
Lucente
G
G
Luisi
G
G
Pinnen
F
F
Rossi
D
D
D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D005978:Glutathione / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D010084:Oxidation-Reduction; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013552:Swine; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors
D001372:Aza Compounds; D004791:Enzyme Inhibitors; C097935:gamma-(gamma-azaglutamyl)cysteinylglycine; D005723:gamma-Glutamyltransferase; D005978:Glutathione