Different inhibitory effects of 5-S-glutathionyl-beta-alanyl-L-dopa (5-S-GA-L-D) analogues on autophosphorylation and substrate phosphorylation of Src protein tyrosine kinase

Starting with 5-S-glutathionyl-beta-alanyl-L-dopa (1) and 5- S-glutathionyl -beta-alanyl-dopamine (2), a series of analogues with truncated glutathiony l and beta-alanyl-dopa moieties were synthesized, and their inhibitory effe cts on autophosphorylation and substrate phosphorylation reaction by c-Src and by epidermal growth factor receptor (EGFR) were evaluated. When the glu tamyl residue was removed, the inhibitory effects on v-Src autophosphorylat ion decreased about 4- to 5-fold, and concomitant removal of the glutamyl a nd beta-alanyl residues resulted in a 40- to 60-fold decrease in the inhibi tion of v-Src autophosphorylation, On the other hand, these modifications h ad little effect on the inhibitory activity of substrate (Raytide(TM)) phos phorylation by c-Src, Interestingly, 5-S-cysteinyl dopamine inhibited the S rc substrate phosphorylation reaction with comparable potency to that of ge nistein, Nonpeptide lipophilic derivatives had a similar inhibition on v-Sr c autophosphorylation but decreased inhibitory effects on substrate phospho rylation when compared to the lead compounds. Most compounds showed little effect on substrate phosphorylation by EGFR.