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.
Zheng
Z B
ZB
Nagai
S
S
Iwanami
N
N
Suh
D Y
DY
Kobayashi
A
A
Hijikata
M
M
Natori
S
S
Sankawa
U
U
D004298:Dopamine / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005978:Glutathione / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D007980:Levodopa / Q000031:analogs & derivatives* / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D013329:Structure-Activity Relationship; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*