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 synth etic 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 relea se in vitro, but the others were inactive. Since Boc-L-Ser-L-Pro-OH wa s more effective than H-L-Ser-L-Pro-OH, 7 related dipeptides with N-ac ylation 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 compound s 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 (B owes) cells. In rats, FK-5, N-stearoyl-D-Ser-L-Pro-OH (FK-8) and N-ste aroyl-D-Ser-L-Pro-OEt (FK-10) enhanced the fibrinolytic activity two-f old. FK-5 and FK-8 also exhibited strong hemolytic activity, but FK-10 did not induce hemolysis. Therefore, FK-10 was examined in rabbits. A fter the injection of this compound, the fibrinolytic activity in the euglobulin fraction was markedly enhanced without accompanying hemolys is. Thus, FK-10 potently enhances fibrinolytic activity both in vitro and in vivo.