Synthesis and activity of γ-(L-γ-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 γ-glutamyl peptide bond. Thus, the target compound, γ-(L-γ-azaglutamyl)-S-(p-bromobenzyl)-L-cysteinylglycine6, 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 γ-glutamyltranspeptidase enzyme.