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

Abstract

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).

• Authors: E Kasafírek, M Rybák, I Krejcí, A Sturc, E Krepela, A Sedo
• Journal: Life sciences (Life Sci) Vol. 50 Issue 3 Pg. 187-93 ( 1992) ISSN: 0024-3205 [Print] Netherlands
• PMID: 1530983 (Publication Type: Journal Article)

Chemical References

• Antibiotics, Antineoplastic
• Oligopeptides
• Piperazines
• Spiro Compounds
• 3,6-bis(5-chloro-2-piperidyl)-2,5-piperazinedione
• Kallikreins
• Fibrinolysin

Topics

• 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, pharmacology)
• Piperazines (chemistry)
• Spiro Compounds (administration & dosage, blood, chemical synthesis)