Synthetic dipeptide, N-stearoyl-D-Ser-L-Pro-OEt, induces release of tissue-type plasminogen activator in cultured cells and in experimental animals.
The tissue-type plasminogen activator (t-PA)-releasing action of synthetic dipeptides containing Gly, Ser or Pro was investigated. Among 10 dipeptides, Boc-L-Ser-L-Pro-OH and H-L-Ser-L-Pro-OH induced t-PA release in vitro, but the others were inactive. Since Boc-L-Ser-L-Pro-OH was more effective than H-L-Ser-L-Pro-OH, 7 related dipeptides with N-acylation were synthesized. Five of them enhanced the release of t-PA; N-stearoyl-L-Ser-L-Pro-OH (FK-5) had the greatest effect. Four compounds were further examined for activity to enhance the release of t-PA in rats. FK-5 produced a two-fold increase in fibrinolytic activity, and N-palmitoyl-L-Ser-L-Pro-OH (FK-4) also markedly enhanced the release of t-PA. Since FK-5 caused severe hemolysis, 7 analogues of FK-5 were synthesized. All of them enhanced the release of t-PA from melanoma (Bowes) cells. In rats, FK-5, N-stearoyl-D-Ser-L-Pro-OH (FK-8) and N-stearoyl-D-Ser-L-Pro-OEt (FK-10) enhanced the fibrinolytic activity two-fold. FK-5 and FK-8 also exhibited strong hemolytic activity, but FK-10 did not induce hemolysis. Therefore, FK-10 was examined in rabbits. After the injection of this compound, the fibrinolytic activity in the euglobulin fraction was markedly enhanced without accompanying hemolysis. Thus, FK-10 potently enhances fibrinolytic activity both in vitro and in vivo.
Research Institute, Fuji Chemical Industries, Ltd., Toyama, Japan.
T
T
Okayama
M
M
Nakano
S
S
Odake
M
M
Hagiwara
T
T
Morikawa
S
S
Ueshima
K
K
Okada
H
H
Fukao
O
O
Matsuo
D000595:Amino Acid Sequence; D000818:Animals; D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D008297:Male; D008546:Melanoma, Experimental / Q000378:metabolism; D008969:Molecular Sequence Data; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013228:Stearates / Q000138:chemical synthesis* / Q000494:pharmacology*; D010959:Tissue Plasminogen Activator / Q000097:blood / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D004151:Dipeptides; D013228:Stearates; C090381:N-stearoyl-seryl-proline ethyl ester; D010959:Tissue Plasminogen Activator