Two-step generation of spirocyclic dipeptides from linear peptide ethyl ester precursors

• Published in: Life sciences (1973) Vol. 50; no. 3; p. 187
• Main Authors: Kasafírek, E, Rybák, M, Krejcí, I, Sturc, A, Krepela, E, Sedo, A
• Format: Journal Article
• Language: English
• Published: Netherlands 1992
• Subjects: Amino Acid Sequence; Animals; Antibiotics, Antineoplastic - chemistry; Chromatography, Thin Layer; Fibrinolysin - biosynthesis; Kallikreins - biosynthesis; Memory - drug effects; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Oligopeptides - chemistry; Oligopeptides - pharmacology; Piperazines - chemistry; Spiro Compounds - administration & dosage; Spiro Compounds - blood; Spiro Compounds - chemical synthesis
• ISSN: 0024-3205
• DOI: 10.1016/0024-3205(92)90271-P

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).