Pharmaceutical Research

, Volume 12, Issue 3, pp 323–328 | Cite as

The Importance of Structural Factors on the Rate and the Extent of N,O-acyl Migration in Cyclic and Linear Peptides

  • Reza Oliyai
  • Teruna J. Siahaan
  • Valentine J. Stella


The chemistry associated with the process of N,O-acyl migration was explored in both cyclic and linear peptides under aqueous acid conditions. The importance of backbone cyclization and N-methylation of the peptide bond on the kinetics of N,O-acyl migration in a series of linear and cyclic peptides related in structure to cyclosporin A (CsA) were examined. The similarity in the chemical reactivity of the cyclic peptide [MeLeu (3-OH)]1-CsA and the corresponding linear peptide [Val-MeLeu (3-OH)-Abu], suggested that for this series, cyclization of the peptide backbone may not play an important role in controlling the kinetics of N,O-acyl migration. In contrast, the disparity in the chemical reactivity of tripeptides [Val-MeLeu (3-OH)-Abu] and [Val-Leu (3-OH)-Abu], indicated that N-methylation of amide bond significantly impacted the kinetics. Various hypothesis are proposed to account for this observation.

acyl migration peptides cyclosporin stability 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    M. C. Manning, K. Patel, and R. T. Borchardt. Stability of protein pharmaceuticals. Pharm. Res. 6:903–918 (1989).Google Scholar
  2. 2.
    R. Oliyai and V. J. Stella. Kinetics and mechanism of isomerization of cyclosporin A. Pharm. Res. 9:617–622 (1992).Google Scholar
  3. 3.
    R. Oliyai, M. Safadi, P. G. Meier, M.-K. Hu, D. H. Rich, and V. J. Stella. Kinetics of acid-catalyzed degradation of cyclosporin A and its analogs in aqueous solution. Int. J. Peptide & Protein Res. 43:239–247 (1994).Google Scholar
  4. 4.
    D. H. Rich, M. K. Dhaon, B. Dunlap and P. F. Miller. Synthesis and antimitogenic activities of four analogues of cyclosporin A modified in the 1-position. J. Med. Chem. 29:978–984 (1986).Google Scholar
  5. 5.
    J. R. McDermott and M. L. Benoiton. N-methylamino acids in peptide synthesis. V. The synthesis of N-tert-butyloxycarbonyl, N-methylamino acids by N-methylation. Can. J. Chem. 55:906–910 (1977).Google Scholar
  6. 6.
    S. Chakrabarti and T. J. Siahaan. Stability of linear and cyclic RGD peptides. Pharm. Res. 10:S93 (1993).Google Scholar
  7. 7.
    D. S. Egglestone, P. W. Baures, C. E. Peishoff and Kenneth D. Kopple. Conformations of cyclic heptapeptides: Crystal structure and computational studies of evolidine. J. Am. Chem. Soc. 113:4410–4416 (1991).Google Scholar
  8. 8.
    T. J. Siahaan, S. Chakrabarti and D. Vander Velde. Conformational study of cyclo(1,5)-Ac-Pen-Arg-Gly-Asp-Cys-NH2 in water by NMR and molecular dynamics. Biochem. Biophys. Res. Comm. 187:1042–1047 (1992).Google Scholar
  9. 9.
    E. S. Stevens, N. Sugawara, G. M. Bonora and C. Toniolo. Conformational analysis of linear peptides. 3. Temperature dependence of NH chemical shifts in chloroform. J. Am. Chem. Soc. 102:7048–7050 (1980).Google Scholar
  10. 10.
    K. Wüthrich. Modern NMR of proteins and Nucleic acids. Wiley, New York (1986).Google Scholar
  11. 11.
    J. D. Aebi, D. T. Deyo, C. W. Sun, D. Guillaume, B. Dunlap and D. H. Rich. Synthesis, conformation, and immunosuppressive activities of three analogues of cyclosporin A modified in the 1-position. J. Med. Chem. 33:999–1009 (1990).Google Scholar
  12. 12.
    R. A. Wiley and D. H. Rich. Peptidomimetics derived from natural products. Med. Res. Rev. 13:327–384 (1993).Google Scholar
  13. 13.
    F. Marcus. Preferential cleavage at aspartyl-prolyl peptide bonds in dilute acid. Int. J. Peptide & Protein Res. 25:542–546 (1985).Google Scholar
  14. 14.
    M. Landon. Cleavage at aspartyl-prolyl bonds. Methods Enzymol. 47:145–149 (1977).Google Scholar
  15. 15.
    V. Somayaji and R. S. Brown. Distorted amides as models for activated peptide N − C = O units produced during enzyme-catalyzed acyl transfer reactions. The mechanism of hydrolysis of 3,4-dihydro-2-oxo-1,4-ethanoquinoline and 2,3,4,5-tetrahydro-2-oxo-1,5-ethanobenzazepine. J. Org. Chem. 51:2676–2686 (1986).Google Scholar
  16. 16.
    V. Somayaji, K. I. Skorey, R. S. Brown and R. G. Ball. Molecular structure of 2,3,4,5-tetrahydro-2-oxo-1,5-ethanobenzazepine and its reaction with β-amino alcohols as a model for the acylation step of serine proteases. J. Org. Chem. 51:4866–4872 (1986).Google Scholar
  17. 17.
    J. W. Keillor and R. S. Brown. Attack of zwitterionic ammonium thiolates on a distorted anilide as a model for the acylation of papin by amides. A simple demonstration of a bell-shaped pH/rate profile. J. Am. Chem. Soc. 114:7983–7989 (1992).Google Scholar
  18. 18.
    A. J. Bennet, Q-P Wang, H. Slebocka-Tilk, V. Somayaji and R. S. Brown. Relationship between amidic distortion and ease of hydrolysis in base. If amidic resonance does not exist, then what accounts for the accelerated hydrolysis of distorted amides? J. Am. Chem. Soc. 112:6383–6385 (1990).Google Scholar
  19. 19.
    H. Slebocka-Tilk, A. J. Bennet, H. J. Hogg and R. S. Brown. Predominant 18O exchange accompanying base hydrolysis of a tertiary toluamide: N-ethyl-N-(trifluoroethyl)toluamide. Assessment of the factors that influence partitioning of anionic tetrahedral intermediates. J. Am. Chem. Soc. 113:1288–1294 (1991).Google Scholar

Copyright information

© Plenum Publishing Corporation 1995

Authors and Affiliations

  • Reza Oliyai
    • 1
  • Teruna J. Siahaan
    • 1
  • Valentine J. Stella
    • 1
  1. 1.Department of Pharmaceutical ChemistryThe University of KansasLawrence

Personalised recommendations