Two-step generation of spirocyclic dipeptides from linear peptide ethyl ester precursors.
Linear tri- and tetrapeptide precursors of 2,5-piperazinedione were prepared and their conversion to spirocyclic dipeptidase enzymes, the spirocyclic dipeptides (SpDp) were generated from the precursors by a two-step mechanism consisting in the proteolytic release of the C-terminal dipeptide ethyl ester and its subsequent spontaneous cyclization. After intraperitoneal administration of urokinase and Ac-Leu-Lys-Gly-Acp-OEt, a SpDp precursor targeted to endogenous plasmin, or the administration of the activated Hageman factor fragment and Ac-Leu-Arg-Ala-Acp-OEt, a SpDp precursor, targeted to endogenous kallikrein, the generated corresponding C-terminal dipeptide ethylester intermediates and SpDp, cyclo(Gly-Acp) and cyclo (Ala-Acp), respectively, were detected in the blood serum of C57B1 mice. Suppression of partial amnesia induced by sodium nitrite was observed in rats where it was subcutaneously administered with H-Leu-Ala-Acp-OEt, a peptide precursor of alaptide, the active SpDp, i.e. cyclo(1-amino-1-cyclopentanecarbonyl-L-alanyl).
Kasafírek
E
E
Research Institute for Pharmacy and Biochemistry, Prague, Czechoslovakia.
Rybák
M
M
Krejcí
I
I
Sturc
A
A
Krepela
E
E
Sedo
A
A
D000595:Amino Acid Sequence; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry*; D002855:Chromatography, Thin Layer; D005341:Fibrinolysin / Q000096:biosynthesis; D007610:Kallikreins / Q000096:biosynthesis; D008568:Memory / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D010879:Piperazines / Q000737:chemistry*; D013141:Spiro Compounds / Q000008:administration & dosage / Q000097:blood / Q000138:chemical synthesis*
D000903:Antibiotics, Antineoplastic; D009842:Oligopeptides; D010879:Piperazines; D013141:Spiro Compounds; C003905:3,6-bis(5-chloro-2-piperidyl)-2,5-piperazinedione; D007610:Kallikreins; D005341:Fibrinolysin