Letters in Peptide Science

, Volume 5, Issue 2–3, pp 83–86 | Cite as

1,2,5-Trisubstituted 1,4-diazepine-3-one: A novel dipeptidomimetic molecular scaffold

  • Iris S. Weitz
  • Maria Pellegrini
  • Miriam Royo
  • Dale F. Mierke
  • Michael Chorev
Article
  • 51 Downloads

Summary

The continuing effort to transform bioactive peptides into non-peptide peptidomimetics of therapeutic potential requires a diversity of tools such as molecular scaffolds, pseudopeptide modifications, and conformation mimetics. To this end, a novel polyfunctional monoheterocyclic system, 1,2,5-trisubstituted hexahydro-3-oxo-1H-1,4-diazepine ring (DAP), was designed. The linear precursor for the DAP was generated through a reductive alkylation step including a modified side chain and an α-amino function of two amino acid derivatives. Structural analysis of model diastereomeric DAPs, employing1H and13C NMR and computer simulation, revealed the conformational preferences of this system. The structural similarities to the 1,4-benzodiazepine, a common molecular scaffold for many non-peptidic peptidomimetic agents, and the pronounced dipeptidomimetic character of the DAP system offer a new powerful tool to medicinal chemists engaged in rational peptide-based drug design.

Key words

1,4-diazepine-3-one dipeptidomimetic molecular scaffold 

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References

  1. 1.
    Kemp, D.S. and McNamara, P., Tetrahedron Lett., 23 (1982) 3761.CrossRefGoogle Scholar
  2. 2.
    Freidinger, R.M., Schwenk-Perlow, D. and Veber, D.F., J. Org. Chem., 47 (1982) 104.CrossRefGoogle Scholar
  3. 3.a.
    DiMaio, J. and Belleau, B., J. Chem. Soc., Perkin Trans, I (1989) 1687.CrossRefGoogle Scholar
  4. 3.b.
    Yamashita, T., Kojima, Y., Hirotsu, K. and Ohsuka, A., Int. J. Pept. Protein Res., 33 (1989) 110.CrossRefGoogle Scholar
  5. 4.a.
    Hölzemann, G., Kontakte (Darmstadt) 1 (1991) 3.Google Scholar
  6. 4.b.
    Hölzemann, G., Kontakte (Darmstadt) 2 (1991) 55.Google Scholar
  7. 4.c.
    Sato, M., Lee, J.Y.H., Nakanishi, H., Johnson, M.E., Chrusciel, R.A. and Kahn, M., Biochem. Biophys. Res. Commun., 187 (1992) 999.PubMedCrossRefGoogle Scholar
  8. 4.d.
    Callahan, J.F., Newlander, K.A., Burgess, J.L., Eggleston, D.S., Nichols, A., Wong, A. and Huffman, W.F., Tetrahedron, 49 (1993) 3479.CrossRefGoogle Scholar
  9. 5.
    Farmer, P.S., In Ariens, E.J. (Ed.) Drug Design, Vol. X, Academic Press, New York, NY, 1980, pp. 19–43.Google Scholar
  10. 6.
    Hirschmann, R., Nicolaou, K.C., Pietranico, S., Salvino, J., Leahy, E.M., Sprengeler, P.A., Furst, G., Smith III, A.B., Strader, C.D., Cascieri, M.A., Candelore, M.R., Donaldson, C., Vale, W. and Maechler, L., J. Am. Chem. Soc., 114 (1992) 9217.CrossRefGoogle Scholar
  11. 7.
    Chorev, M., Roubini, E., Gilon, C. and Selinger, Z., Biopolymers, 31 (1991) 725.PubMedCrossRefGoogle Scholar
  12. 8.
    DeWitt, S.H., Kiely, J.S., Stankovic, C.J., Schroeder, M.C., Cody, D.M.R. and Pavia, M.R., Proc. Natl. Acad. Sci. USA, 90 (1993) 6909.PubMedCrossRefGoogle Scholar
  13. 9.
    Sawyer, T.K., In Taylor, M.D. and Amidon, G.L. (Eds.) Peptides-Based Drug Design Controlling Transport and Metabolism, American Chemical Society, Washington, DC, 1995, pp. 385–422, and references therein.Google Scholar
  14. 10.
    Weitz, I.S., Pellegrini, M., Mierke, D.F. and Chorev, M., J. Org. Chem., 62 (1997) 2527.PubMedCrossRefGoogle Scholar
  15. 11.
    Pellegrini, M., Weitz, I.S., Chorev, M. and Mierke, D.F., J. Am. Chem. Soc., 43 (1997) 2430.CrossRefGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1998

Authors and Affiliations

  • Iris S. Weitz
    • 1
  • Maria Pellegrini
    • 2
  • Miriam Royo
    • 3
  • Dale F. Mierke
    • 2
    • 4
  • Michael Chorev
    • 1
    • 3
  1. 1.Pharmaceutical Chemistry Department, School of Pharmacy, Faculty of MedicineThe Hebrew University of JerusalemJerusalemIsrael
  2. 2.Carlson School of ChemistryClark UniversityWorcesterU.S.A.
  3. 3.Division of Bone and Mineral Metabolism, Thorndike and Charles A. Dana Laboratories Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonU.S.A.
  4. 4.Department of Pharmacology and Molecular ToxicologyUniversity of Massachusetts, Medical CenterWorcesterU.S.A.

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