Synthesis and activity of gamma-(L-gamma-azaglutamyl)-S-(p-bromobenzyl)-L-cysteinylglycine: a metabolically stable inhibitor of glyoxalase I.
The inhibition of glyoxalase I enzyme to increase cellular levels of methylglyoxal has been developed as a rationale for the production of anticancer agents. Synthesis of a peptidomimetic analog of the previously prepared potent glyoxalase inhibitor, S-(p-bromobenzyl)glutathione (PBBG), was accomplished by inserting a urea linkage, NH-CO-NH, to replace the gamma-glutamyl peptide bond. Thus, the target compound, gamma-(L-gamma-azaglutamyl)-S-(p-bromobenzyl)-L-cysteinylglycine 6, was a potent inhibitor of glyoxalase I with almost no loss of activity when compared to PBBG. However, unlike PBBG, 6 was completely resistant to enzymatic degradation by kidney homogenate or by purified gamma-glutamyltranspeptidase enzyme.
Vince
R
R
College of Pharmacy, Department of Medicinal Chemistry, University of Minnesota, Minneapolis 55455-0343, USA.
Brownell
J
J
Akella
L B
LB
D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis*; D002855:Chromatography, Thin Layer; D005978:Glutathione / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors*; D051379:Mice; D008956:Models, Chemical; D013997:Time Factors
D001372:Aza Compounds; C097935:gamma-(gamma-azaglutamyl)cysteinylglycine; C020233:S-(4-bromobenzyl)glutathione; D007791:Lactoylglutathione Lyase; D005978:Glutathione