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 glutathionyl and beta-alanyl-dopa moieties were synthesized, and their inhibitory effects on autophosphorylation and substrate phosphorylation reaction by c-Src and by epidermal growth factor receptor (EGFR) were evaluated. When the glutamyl residue was removed, the inhibitory effects on v-Src autophosphorylation decreased about 4- to 5-fold, and concomitant removal of the glutamyl and beta-alanyl residues resulted in a 40- to 60-fold decrease in the inhibition of v-Src autophosphorylation. On the other hand, these modifications had little effect on the inhibitory activity of substrate (Raytide) phosphorylation by c-Src. Interestingly, 5-S-cysteinyl dopamine inhibited the Src substrate phosphorylation reaction with comparable potency to that of genistein. Nonpeptide lipophilic derivatives had a similar inhibition on v-Src autophosphorylation but decreased inhibitory effects on substrate phosphorylation when compared to the lead compounds. Most compounds showed little effect on substrate phosphorylation by EGFR.