Synthesis and cistrans isomerism in novel Leu-enkephalin-related peptidomimetics containing N-glycated glycine residues

(Note: The full text of this document is currently only available in the PDF Version )

Mare Čudić, Jaroslav Horvat, Mikael Elofsson, Karl-Erik Bergquist, Jan Kihlberg and Štefica Horvat

The influence of a new peptoid residue on amide-bond stereochemistry has been explored via the synthesis and NMR analysis of novel peptidomimetics related to the endogenous opioid pentapeptide Leu-enkephalin (H-Tyr-Gly-Gly-Phe-Leu-OH). The compounds studied include protected and unprotected enkephalin analogues N-alkylated at either the second (Gly2) or both the second and the third (Gly2,Gly3) amino acid residues with a 6-deoxy-D-galactose moiety. The syntheses of the mono- (7) and the bis-glycated pentapeptide (11) were performed in a stepwise manner in solution by employing N-glycated glycine as the building block. The relative populations of the cis and trans isomers in the compounds studied were estimated by NMR spectroscopy. In the fully protected N-glycated dipeptide 3 the most abundant isomer (64%) was shown to contain a cis Tyr1-(X)Gly2 amide bond. NMR analysis of mono-N-glycated pentapeptide 6 provided evidence that elongation of the peptide chain disfavours the cis and augments the trans isomer population (cistrans 35∶65). For the unprotected monoglycated peptides 5 and 7 both the α- and β-pyranose forms of the galactose moieties were detected, the β-pyranose tautomer being the most abundant (≈70%). Removal of the protecting groups decreased the proportion of cis-rotamers relative to the corresponding protected peptides 3 and 6. The NMR spectra of enkephalin-related peptides 8–11, which contain two N-glycated glycine residues, were extremely complex; both proximal and distal isomerization effects were observed. For the bis-glycated tripeptide 8 significant amounts of both the cis and trans rotamers were observed for the Tyr1-(X)Gly2 and (X)Gly2-(X)Gly3 peptide bonds. In the fully protected pentapeptide 10 the configurational equilibrium was markedly shifted in favour of the trans isomers; only 15% of the cis isomer was observed for the Tyr1-(X)Gly2 bond, whereas the (X)Gly2-(X)Gly3 bond was completely in the trans configuration.


  1. G. A. Olson, R. D. Olson and A. J. Kastin, Peptides, 1996, 17, 1421 CrossRef CAS.
  2. P. W. Schiller, in Medicinal Chemistry for the 21st Century, ed. C. G. Wermuth, N. Koga, H. König and B. W. Metcalf, Blackwell, Oxford, IUPAC, 1992, pp. 215–232 Search PubMed.
  3. M. Skurić, J. Horvat, Š. Horvat, N. N. Chung and P. W. Schiller, Int. J. Pept. Protein Res., 1994, 43, 402 Search PubMed and references cited therein.
  4. Š. Horvat, M. Roščić, L. Varga-Defterdarović and J. Horvat, J. Chem. Soc., Perkin Trans. 1, 1998, 909 RSC.
  5. R. Polt, F. Porreca, L. Z. Szabo, E. J. Bilsky, P. Davis, T. J. Abbruscato, T. P. Davis, R. Horvath, H. I. Yamamura and V. J. Hruby, Proc. Natl. Acad. Sci. USA, 1994, 91, 7114 CAS.
  6. E. G. von Roedern, E. Lohof, G. Hessler, M. Hoffmann and H. Kessler, J. Am. Chem. Soc., 1996, 118, 10 156 CrossRef CAS.
  7. B. Drouillat, B. Kellam, G. Dekany, M. S. Starr and I. Toth, Bioorg. Med. Chem. Lett., 1997, 7, 2247 CrossRef CAS.
  8. A. Jakas and Š. Horvat, J. Chem. Soc., Perkin Trans. 2, 1996, 789 RSC.
  9. Š. Horvat, A. Jakas, E. Vass, J. Samu and M. Hollósi, J. Chem. Soc., Perkin Trans. 2, 1997, 1523 RSC.
  10. J. Rhodes, B. Zheng and C. A. Morrison, Ann. N.Y. Acad. Sci., 1995, 754, 169 CAS.
  11. R. Carubelli, Experientia, 1995, 51, 121 Search PubMed.
  12. R. E. Arrick, D. C. Baker and D. Horton, Carbohydr. Res., 1973, 26, 441 CrossRef CAS.
  13. J. Coste, E. Frérot and P. Jouin, J. Org. Chem., 1994, 59, 2437 CrossRef CAS.
  14. P. Dais and A. S. Perlin, Carbohydr. Res., 1987, 169, 159 CrossRef CAS.
  15. S. J. Angyal, Carbohydr. Res., 1994, 263, 1 CrossRef CAS.
  16. B. Vitoux, A. Aubry, M. T. Cung and M. Marraud, Int. J. Pept. Protein Res., 1986, 27, 617 Search PubMed.
  17. T. Ozawa, Y. Isoda, H. Watanabe, T. Yuzuri, H. Suezawa, K. Sakakibara and M. Hirota, Magn. Reson. Chem., 1997, 35, 323 CrossRef CAS.
  18. M. Nishio, Y. Umezawa, M. Hirota and Y. Takeuchi, Tetrahedron, 1995, 51, 8665 CrossRef CAS.