Amino Acids

, Volume 17, Issue 3, pp 257–265 | Cite as

Novel glutathione analogues containing the dithiol and disulfide form of the Cys-Cys dyad

  • A. Calcagni
  • G. Lucente
  • G. Luisi
  • F. Pinnen
  • D. Rossi
Full Papers


The glutathione analogue γ-(H-Glu-OH)-
-OH (5), containing the 8-membered disulfide ring-
replacing the native -Cys-Gly fragment, has been synthesized and characterized together with its reduced dithiol form γ-(H-Glu-OH)-Cys-Cys-OH (6).


Amino acids Conformational constraint Cyclic disulfides -Cys-Cys-peptides Dipeptide mimetics Dithiols Glutathione analogues 



1,8-diazabicyclo [5.4.0] undec-7-ene;






tetrahydrofuran; (n-Bu)3P, tri-n-butylphosphine


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  1. Avizonis DZ, Farr-Jones S, Kosen PA, Basus VJ (1996) Conformations and dynamics of the essential cysteinyl-cysteine ring derived from the acetylcholine receptor. J Am Chem Soc 118: 13031–13039Google Scholar
  2. Brady SF, Paleveda WJ Jr, Arison BH, Saperstein R, Brady EJ, Raynor K, Reisine T, Veber DF, Freidinger RM (1993) Approaches to peptidomimetics which serve as surrogates for thecis amide bond: novel disulfide-constrained bicyclic hexapeptide analogs of somatostatin. Tetrahedron 49: 3449–3466Google Scholar
  3. Calcagni A, Duprè S, Lucente G, Luisi G, Pinnen F, Rossi D (1995) Synthesis and activity of the glutathione analogueγ-(l-γ-azaglutamyl)-l-cysteinyl-glycine. Int J Peptide Protein Res 46: 434–439Google Scholar
  4. Calcagni A, Duprè S, Lucente G, Luisi G, Pinnen F, Rossi D, Spirito A (1996) Synthesis and activity of the glutathione analoguegg-(l-γ-oxaglutamyl)-l-cysteinyl-glycine. Arch Pharm 329: 498–502Google Scholar
  5. Capasso S, Mattia C, Mazzarella L, Puliti R (1977) Structure of acis-peptide unit: molecular conformation of the cyclic disulphide L-cysteinyl-L-cysteine. Acta Cryst B33: 2080–2083Google Scholar
  6. Capasso S, Mazzarella L, Tancredi T, Zagari A (1984) Synthesis and properties of L-cysteinyl-L-cysteine disulfides. Biopolymers 23: 1085–1097Google Scholar
  7. Chan C-D, Waki M, Ahmad M, Meienhofer J, Lundell EO, Haug JD (1980) Preparation and properties ofN a-9-fluorenylmethyloxycarbonylamino acids bearingtert-butyl side chain protection. Int J Peptide Protein Res 15: 59–66Google Scholar
  8. Chandrasekaran R, Balasubramanian R (1969) Stereochemical studies of cyclic peptides. VI. Energy calculations of the cyclic disulfide cysteinyl cysteine. Biochim Biophys Acta 188: 1–9PubMedGoogle Scholar
  9. Chen W-J, Lee DY, Armstrong RN (1986) N4-(Malonyl-D-cysteinyl)-L-2,4-diaminobutyrate: the end-group-modified retro-inverso isomer of glutathione. J Org Chem 51: 2848–2850Google Scholar
  10. Cumberbatch S, North M, Zagotto G (1993) The synthesis and conformational analysis of a pair of diastereomeric, conformationally constrained peptides with opposite amide bond geometries. Tetrahedron 49: 9049–9066Google Scholar
  11. Douglas KT (1989) Chemical synthesis of glutathione and analogs. In: Dolphin D, Poulson R, Avramovic O (eds) Offprints from glutathione: chemical, biochemical and medical aspects - Part A. John Wiley, New York, pp 243–279Google Scholar
  12. Embrey KJ, Mehta A, Carrington SJ, Jaouhari R, Mckie JH, Douglas KT (1994) Use of transferred nuclear-Overhauser-effect spectroscopy to measure the bound conformation of a disulphide-replaced analogue of glutathione disulphide as an inhibitor of yeast glutathione reductase. Eur J Biochem 221: 793–799PubMedGoogle Scholar
  13. Gillespie P, Cicariello J, Olson GL (1997) Conformational analysis of dipeptide mimetics. Biopolymers 43: 191–217Google Scholar
  14. Goodman M, Zhang J (1997) Peptidomimetic building blocks for drug design. Chemtracts-Org Chem 10: 629–645Google Scholar
  15. Gröger H, Hatam M, Kintscher J, Martens J (1996) Synthesis of glutathione analogues, peptide nucleic acids and phosphonooligopeptides from heterocyclic imines. Synth Commun 26: 3383–3394Google Scholar
  16. Hanessian S, McNaughton-Smith G, Lombart H-G, Lubell WD (1997) Design and synthesis of conformationally constrained amino acids as versatile scaffolds and peptide mimetics. Tetrahedron 53: 12789–12854Google Scholar
  17. Hata Y, Matsuura Y, Tanaka N, Ashida T, Kakudo M (1977)tert-Butyloxycarbonyl-L-cysteinyl-L-cysteine disulfide methyl ester. Acta Cryst B33: 3561–3564Google Scholar
  18. Horne A, North M, Parkinson JA (1993) The conformation of cyclo-[(R)-cysteinyl-(R)-cysteine] in solution. Tetrahedron 49: 5891–5904Google Scholar
  19. Izumiya N, Greenstein JP (1954) Studies on polycysteine peptides and proteins. I. Isomeric cystinylcystine peptides. Arch Biochem Biophys 52: 203–216Google Scholar
  20. Kamber B (1971) Cystinpeptide aus (S-Acetamidomethyl-Cystein)-pepttden durch Oxidation mit Jod: die Synthese vonCyclo-L-Cystin. Helv Chim Acta 54: 398–422PubMedGoogle Scholar
  21. Kao PN, Karlin A (1986) Acetylcholine receptor binding site contains a disulfide crosslink between adjacent half-cystinyl residues. J Biol Chem 261: 8085–8088PubMedGoogle Scholar
  22. Liff MI, Siddiqui SS (1996) NMR evidence of formation of cyclocystine loops in peptide models of the high sulfur proteins from wool. Int J Biol Macromol 19: 139–143PubMedGoogle Scholar
  23. Luisi G, Calcagni A, Pinnen F (1993) ψ(SO2-NH) Transition state isosteres of peptides. Synthesis of the glutathione disulfide analogue [Glu-ψ)(SO2-NH)-Cys-Gly]2. Tetrahedron Lett 34: 2391–2392Google Scholar
  24. Mez HC (1974) Cyclo-L-cystine-acetic acid. Cryst Struct Commun 3: 657–660Google Scholar
  25. Miller SM, Moore MJ, Massey V, Williams CH, Jr, Distefano MD, Ballou DP, Walsh CT (1989) Evidence for the participation of Cys558 and Cys559 at the active site of mercuric reductase. Biochemistry 28: 1194–1205PubMedGoogle Scholar
  26. Mitra AK, Chandrasekaran R (1984) Conformational flexibilities in malformin A. Briopolymers 23: 2513–2524Google Scholar
  27. Ovchinnikov Yu A, Lipkin VM, Shuvaeva TM, Bogachuk AP, Shemyakin VV (1985) Complete amino acid sequence ofγ-subunit of the GTP-binding protein from cattle retina. FEBS Letters 179: 107–110PubMedGoogle Scholar
  28. Prorok M, Lawrence DS (1990) An affinity label of absolute peptidic origin. J Am Chem Soc 112: 8626–8627Google Scholar
  29. Shao H, Lee C-W, Zhu Q, Gantzel P, Goodman M (1996)β,β-Dimethylcyclolanthionines, new constrained dipeptide mimetics: synthesis, crystal structures, and conformational studies. Angew Chem Int Ed Engl 35: 90–92Google Scholar
  30. Shreder K, Zhang L, Goodman M (1998) Synthesis of a constrained enkephalin analog to illustrate a novel route to the piperazinone ring structure. Tetrahedron Lett 39: 221–224Google Scholar
  31. Siedler F, Rudolph-Böhner S, Doi M, Musiol H-J, Moroder L (1993) Redox potentials of active-site bis (cysteinyl) fragments of thiol-protein oxidoreductases. Biochemistry 32: 7488–7495PubMedGoogle Scholar
  32. Sukumaran DK, Prorok M, Lawrence DS (1991) A molecular constraint that generates a cis peptide bond. J Am Chem Soc 113: 706–707Google Scholar
  33. Theriault Y, Cheesman BV, Arnold AP, Rabenstein DL (1984) Nuclear magnetic resonance studies of the acid-base chemistry of amino acids and peptides. IV. Mixed disulfides of cysteine, penicillamine, and glutathione. Can J Chem 62: 1312–1319Google Scholar
  34. White S, Boyd G, Mathews FS, Xia Z-X, Dai W-W, Zhang Y-F, Davidson VL (1993) The active site structure of the calcium-containing quinoprotein methanol dehydrogenase. Biochemistry 32: 12955–12958PubMedGoogle Scholar
  35. Xie X, Creighton DJ (1991) Synthesis and initial characterization ofγ-L-glutamyl-L-thiothreonyl-glycine andγ-L-glutamyl-L-allo-thiothreonyl-glycine as steric probes of the active site of glyoxalase I. Biochem Biophys Res Commun 177: 252–258PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1999

Authors and Affiliations

  • A. Calcagni
    • 1
  • G. Lucente
    • 1
  • G. Luisi
    • 2
  • F. Pinnen
    • 2
  • D. Rossi
    • 1
  1. 1.Dipartimento di Studi Farmaceutici and Centro di Studio per la Chimica del Farmaco del CNRUniversità “La Sapienza”Roma
  2. 2.Istituto di Scienze del FarmacoUniversità “G. D'Annunzio”ChietiItaly

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