Synthesis and activity of novel glutathione analogues containing an urethane backbone linkage

The new GSH analogues H–Glo(–Ser–Gly–OH)–OH ( 5 ), its O -benzyl derivative 4 , and H–Glo(–Asp–Gly–OH)–OH ( 9 ), characterized by the replacement of central cysteine with either serine or aspartic acid, and containing an urethanic fragment as isosteric substitution of the scissile γ-glutamylic junction, have been synthesized and characterized. Their ability to inhibit human GST P1-1 (hGST P1-1) in comparison with H–Glu(–Ser–Gly–OH)–OH and H–Glu(–Asp–Gly–OH)–OH, which are potent competitive inhibitors of rat GST 3-3 and 4-4, has been evaluated. In order to further investigate the effect of the isosteric substitution on the binding abilities of the new GSH analogues 4 , 5 and 9 , the previously reported cysteinyl-containing analogue H–Glo(–Cys–Gly–OH)–OH has been also evaluated as a co-substrate for hGSTP1-1.