Advertisement

Cyclosporine and Analogues — Isolation and Synthesis — Mechanism of Action and Structural Requirements for Pharmacological Activity

  • R. M. Wenger
Part of the Fortschritte der Chemie organischer Naturstoffe / Progress in the Chemistry of Organic Natural Products book series (FORTCHEMIE (closed), volume 50)

Abstract

Cyclosporine (1), originally named “Cyclosporin A” (for nomenclature see section 1.2), is the main component of a new family of cyclic peptides each comprising 11 amino acids. These peptides are produced as secondary fungal metabolites by Cylindrocarpon lucidum Booth and Tolypocladium inflatum Gams. Both strains of fungi imperfecti were isolated from soil samples collected in Wisconsin (USA) and Hardanger Vidda (Norway). The isolation, the culture conditions and the taxonomy of these fungi are reported by Dreyfuss et al. (1).

Keywords

Iodide Benzyl Epoxide Valine Biotransformation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Dreyfuss, M., E. Haerri, H. Hoffmann, H. Kobel, W. Pache, and H. Tscherter: Cyclosporin A and C. New Metabolites from Trichoderma polysporum (Link ex Pers.) Rifai. Eur. J. Appl. Microbiol. 3, 125 (1976).CrossRefGoogle Scholar
  2. 2.
    Borel, J.F., C. Feurer, H.U. Gubler, and H. Staehelin: Biological Effects of Cyclosporin A: A New Antilymphocytic Agent. Agents Actions 6, 468 (1976).CrossRefGoogle Scholar
  3. 3.
    Borel, J.F.: Comparative Study of in vitro and in vivo Drug Effects on Cell-Mediated Cytotoxicity. Immunology 31, 631 (1976).Google Scholar
  4. 4.
    Borel, J.F., C. Feurer, C. Magnee, and H. Staehelin: Effects of the New AntiLymphocytic Peptide Cyclosporin A in Animals Immunology 32, 1017 (1977).Google Scholar
  5. 5.
    Borel, J.F., D. Wiesinger, and H.U. Gubler: Effects of the Antilymphocytic Agent Cyclosporin A in Chronic Inflammation. Europ. J. Rheumatol. Inflammation 1, 237 (1978).Google Scholar
  6. 6.
    Wiesinger, D., and J.F. Borel: Studies on the Mechanism of Action of Cyclosporin A Immunobiol. 156, 454 (1979).Google Scholar
  7. 7.
    Bueding, E., J. Hawkins, and Y.N. Cria: Antischistosomal Effects of Cyclosporin A. Agents Actions 11, 380 (1981).CrossRefGoogle Scholar
  8. 8.
    Thommen-Scott, K.: Antimalarial Activity of Cyclosporin A. Agents Actions 11, 770 (1981).CrossRefGoogle Scholar
  9. 9.
    Moms, P.J.: Cyclosporin A Overview. Transplantation 32, 349 (1981).CrossRefGoogle Scholar
  10. 10.
    Morris, P.J.: The Impact of Cyclosporin A on Transplantation. Advances in Surgery 17, 99 (1984).Google Scholar
  11. 11.
    Calne, R.Y., D.J.G. White, S. Tiuru, D.B. Evans, P. Mcmaster, D.C. Dunn, G.N. Craddock, D.B. Pentlow, and K. Rolles: Cyclosporin A in Patients Receiving Renal Allografts from Cadaver Donors. Lancet ii, 1323 (1978).Google Scholar
  12. 12.
    Powles, R.L., A.J. Barrett, H. Clink, H.E.M. Kay, J. Sloane, and T.J. Mcelwain: Cyclosporin A for the Treatment of GVH-Disease in Man. Lancet ii, 1327 (1978).Google Scholar
  13. 13.
    Kahan, B.D., ed.: Cyclosporine, Biological and Clinical Applications. Orlando: Grune and Stratton 1984; or In: Transplantation Proceedings, Vol. XV, No. 4, suppl. 1 (December) p. 2207 (1983).Google Scholar
  14. 14.
    Schindler, R., ed.: Cyclosporin in Autoimmune Diseases. Berlin-Heidelberg: Springer. 1985.Google Scholar
  15. 15.
    Wenger, R.M.: Chemistry of Cyclosporin. In: Cyclosporin A. p. 19. Amsterdam: Elsevier Biomed. 1982.Google Scholar
  16. 16.
    Wenger, R.M.: Synthesis of Cyclosporine. I. Synthesis of Enantiomerically Pure (2S,3R,4R,6E)-3-hydroxy-4-methyl-2-(methylamino)-6-octenoic Acid Starting from Tartaric Acid. HeIv. Chim. Acta 66, 2308 (1983).Google Scholar
  17. 17.
    Wenger, R.M.: Synthesis of Cyclosporine. Helv. Chim. Acta 67, 502 (1984).CrossRefGoogle Scholar
  18. 18.
    Wenger, R.M.: Synthesis of Cyclosporine and Analogues: Structural Requirements for Immunosuppressive Activity. Angew. Chem. Intern. Ed. Engl. 24, 77 (1985).Google Scholar
  19. 19.
    IUPAC-IUB Joint Commission on Biochemical Nomenclature: Nomenclature and Symbolism for Amino Acids and Peptides, Recommendations 1983. Eur. J. Biochem. 138, 9 (1984).CrossRefGoogle Scholar
  20. 20.
    Borel, J.F., ed.: Ciclosporin. Progress in Allergy, Vol. 38, p. 9. Basel: Karger. 1986.Google Scholar
  21. 21.
    Wenger, R.M., T.G. Payne, and M.H. Schreier: Cyclosporine Chemistry, Structure-Activity Relationships and Mode of Action. In: Progress in Clinical Biochemistry and Medicine, p. 157. Berlin-Heidelberg: Springer. 1986.Google Scholar
  22. 22.
    Rüegger, A., M. Kuhn, H. Lichti, H.R. Loosli, R. Huguenin, CH. Quiquerez, and A. von Wartburg: Cyclosporin A, ein immunosuppressiv wirksamer Peptidmetabolit aus Trichoderma polysporum (Link ex Pers.) Rifai. Helv. Chim. Acta 59, 1075 (1976).CrossRefGoogle Scholar
  23. 23.
    Traber, R., M. Kuhn, A. Rüegger, H. Lichti, H.R. Loosli, and A. von Wartburg: Die Struktur von Cyclosporin C. Helv. C.im. Acta 60, 1247 (1977).CrossRefGoogle Scholar
  24. 24.
    Traber, R., M. Kuhn, H.R. Loose, W. Pache, and A. von Wartburg: Neue Cyclopeptide aus Trichoderma polysporum (Link ex Pers.) Rifai: die Cyclosporine B, D und E. HeIv. Chim. Acta 60, 1568 (1977).CrossRefGoogle Scholar
  25. 25.
    Traber, R., H.R. Loosli, H. Hofmann, M. Kuhnn, and A. von Wartburg: Isolierung und Strukturvermittlung der neuen Cyclosporine E, F, G, H und I. Helv. Chim. Acta 65, 1655 (1982).CrossRefGoogle Scholar
  26. 26.a)
    Traber, R., H. Hofmann, H.R. Loosli, and A. von Wartburg: Cyclosporins, a New Group of Potent Immunoregulators - Structure Activity Relationships. 24th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington D.C., 8–10 Oct. 1984, Poster Presentation, Abstract No. 900.Google Scholar
  27. 26.b)
    von Wartburg A., and R. Traber: Chemistry of the Natural Cyclosporine Metabolites in Progress in Allergy, Vol. 38, p. 28. Basel: Karger. 1986.Google Scholar
  28. 27.
    Kobel, H., and R. Traber: Directed Biosynthesis of Cyclosporins. Eur. J. Appl. Microbiol. Biotechnol. 14, 237 (1982).CrossRefGoogle Scholar
  29. 28.
    Petcher, T.J., H.P. Weber, and A. Ruegger: Crystal and Molecular Structure of an Iodo-Derivative of the Cyclic Undecapeptide Cyclosporin A. Helv. Chim. Acta 59, 1480 (1976).CrossRefGoogle Scholar
  30. 29.
    Cambie, R.C., R.C. Hayward, J.L. Roberts, P.S. Rutledge: Diterpenes. Todocarboxylation of Phyllocladene and Isophyllocladene. J. Chem. Soc. Perkin I, 1, 1120 (1974).Google Scholar
  31. 30.
    Loosli, H.R., H. Kessler, H. Oschkinat, H.P. Weber, T.J. Petcher, and A. Widmer: The Conformation of Cyclosporin A in the Crystal and in Solution. Helv. Chim. Acta 68, 682 (1985).CrossRefGoogle Scholar
  32. 31.
    Chou, P.Y., and G.D. Fasman: I3-Turns in Proteins. J. Mol. Biol. 115, 135 (1977).CrossRefGoogle Scholar
  33. 32.
    Smith, J.A., and L.G. Pease: Reverse Turns in Peptides and Proteins. CRC Critical Reviews in Biochemistry 8, 315 (1980).CrossRefGoogle Scholar
  34. 33.
    Richardson, J.S.: The Anatomy and Taxonomy of Protein Structure. Adv. Protein Chem. 34, 167 (1981).CrossRefGoogle Scholar
  35. 34.
    Richardson, J.S.: A New Twist for Hairpin Turns. Nature 316, 102 (1985).CrossRefGoogle Scholar
  36. 35.
    Pullman, B., and B. Maigret: In: Conformation of Biological Molecules and Polymers, p. 13. New York: Academic Press. 1973.Google Scholar
  37. 36.
    Kuhn, M., and R.M. Wenger: Dihydro-MeBmt Natural and Synthetic. Unpublished results.Google Scholar
  38. 37.
    Wenger, R.M.: N-BOC- and N-Z-isocyclosporine. Unpublished results.Google Scholar
  39. 38.
    Bollinger, P.: Iodination of Cyclosporine. Unpublished results.Google Scholar
  40. 39.
    Voges, R., B. von Wartburg, H.R. Loosli: Tritiated Compounds for in vivo Investigations. Second Intern. Symposium on the Synthesis and Application of Isotopically Labelled Compounds, Kansas City, Sept. 1985.Google Scholar
  41. 40.
    Gams, W.: Tolypocladium, eine Hyphomycetengattung mit geschwollenen Phialiden. Personia 6, 185 (1971).Google Scholar
  42. 41.
    Wood, A.J., G. Maurer, W. Niederberger, and T. Beveridge: Cyclosporine: Pharmacokinetics, Metabolism and Drug Interaction. Transplantation Proceedings 15 (Suppl. 1), 2409 (1983); (or Ref. 13, p. 193 ).Google Scholar
  43. 42.
    Maurer, G., H.R. Loosli, E. Sschreier, and B. Keller: Disposition of Cyclosporine in Several Animal Species and Man. I. Structural Elucidation of its Metabolites. Drug Metabolism and Disposition 12, 120 (1984).Google Scholar
  44. 43.
    Hartman, N.R., L.A. Trimble, J.C. Vederas, and I. Jardine: An Acid Metabolite of Cyclosporine. Biochem. Biophys. Res. Comm. 133, 964 (1985).CrossRefGoogle Scholar
  45. 44.
    Hiestand, P., and B. Ryffel: Pharmacological Activity of Cyclosporine Metabolites. Unpublished results.Google Scholar
  46. 45.
    Kessler, H., H.R. Loosli, and H. Oschkinat: Peptide Conformations: Assignment of 1H, 13C, and 5N-NMR Spectra of Cyclosporin A in CDC13 and C6D6 by a Combination of Homo-and Heteronuclear Two-Dimensional Techniques. Helv. Chim. Acta 68, 661 (1985).CrossRefGoogle Scholar
  47. 46.
    Donatsch, P., E. Abisch, M. Homberger, R. Traber, M. Trapp, and R. Voges: A Radioimmunoassay to Measure Cyclosporin A in Plasma and Serum Samples. J. Immunoassay 2, 19 (1981).CrossRefGoogle Scholar
  48. 47.
    Quesniaux, V., R. Tees, M.H. Schreier, R.M. Wenger, P. Donatsch, M.H.V. van Regenmortel: Monoclonal Antibodies to Ciclosporin. In: Progress in Allergy, Vol. 38, p. 108 (1986).Google Scholar
  49. 48.
    Rosenthaler, J., P. Ball, and H. Münzer: Monoclonal Antibodies to Ciclosporin. Manuscript in preparation.Google Scholar
  50. 49.
    Quesniaux, V., R.M. Wenger, M.H. Schreier, and M.H.V. van Regenmortel: Manuscript in preparation.Google Scholar
  51. 50.
    Kobel, H., H.R. Loosli, and R. Voges: Contribution to Knowledge of the Biosynthesis of Cyclosporin A. Experientia 39, 873 (1983).CrossRefGoogle Scholar
  52. 51.
    Zocher, R., and H. Kleinkauf: Biosynthesis of Enniatin B. Partial Purification and Characterization of the Synthesizing Enzyme and Studies of the Biosynthesis. Biochem. Biophys. Res. Comm. 81, 1162 (1978).CrossRefGoogle Scholar
  53. 52.
    Zocher, R., N. Madry, H. Peeters, and H. Kleinkauf: Biosynthesis of Cyclosporin A. Phytochemistry 23, 549 (1984).CrossRefGoogle Scholar
  54. 53.
    Siegbahn, N., K. Mosbach, K. Grodzki, R. Zocher, N. Madry, and H. Kleinkauf: Covalent Immobilization of the Multienzyme Enniatin Synthetase. Biotechnology Letters 7, 297 (1985).CrossRefGoogle Scholar
  55. 54.
    Zocher, R., U. Keller, and H. Kleinkauf: Enniatin Synthetase, a Novel Type of Multifunctional Enzyme Catalysing Depsipeptide Synthesis in Fusarium oxysporum. Biochemistry 21, 43 (1982).CrossRefGoogle Scholar
  56. 55.
    Zocher, R., T. Nihira, E. Paul, N. Madry, H. Peeters, H. Kleinkauf, and U. Keller: Biosynthesis of Cyclosporin A: Partial purification and Properties of a Multifunctional Enzyme from: Tolypocladium inflatum. Biochemistry 25, 550 (1986).CrossRefGoogle Scholar
  57. 56.
    Schlosser, M., and K.F. Christmann: Mechanismus und Stereochemie der Wittig-Reaktion. Justus Liebigs Ann. Chem. 708, 1 (1967).Google Scholar
  58. 57.
    Seeley, D.A., J. Mcelwee: Stereospecific Synthesis of cis and trans Epoxides from the Same Diol. J. Org. Chem 38, 1691 (1973).CrossRefGoogle Scholar
  59. 58.
    Herb, R.W., D.M. Wieland, and C.R. Johnson: Reactions of Organocopper Reagents with Oxiranes. J. Amer. Chem. Soc. 92, 3813 (1970).CrossRefGoogle Scholar
  60. 59.
    Pfitzner, K.E., and J.G. Moffarr: Sulfoxide-Carbodiimide Reactions. Scope of the Oxidation Reaction. J. Amer. Chem. Soc. 87, 5670 (1965).CrossRefGoogle Scholar
  61. 60.
    Wenger, R.M.: Synthesis of Cyclosporine. Hely. Chim. Acta 66, 2672 (1983).CrossRefGoogle Scholar
  62. 61.
    Mcderniorr, J.R., and N.L. Benoiton: (a) N-methylamino Acids in Peptide Synthesis. Razemization During Deprotection by Saponification and Acidolysis. Can. J. Chem. 51, 2551 (1973); (b) Razemization and Yields in Peptide-Bond Formation. Can. J. Chem. 51, 2562 (1973).Google Scholar
  63. 62.
    Tung, R.D., and D.H. Rich: Bis(2-oxo-3-oxazolidinyl)phosphinic Chloride as a Coupling Reagent for N-alkyl Amino Acids. J. Amer. Chem. Soc. 107, 4342 (1985).CrossRefGoogle Scholar
  64. 63.
    Zaoral, M.: Amino Acids and Peptides. Pivaloyl Chloride as a Reagent in the Mixed Anhydride Snthesis of Peptides. Collect. Czech. Chem. Commun. 27, 1273 (1962).Google Scholar
  65. 64.
    Koenig, W., and R. Geiger: Eine neue Methode zur Synthese von Peptiden. Aktivierung der Carboxylgruppe mit DCCI unter Zusatz von 1-Hydroxybenztriazolen. Chem. Ber. 103, 788 (1970).CrossRefGoogle Scholar
  66. 65.
    Castro, B., J.R. Doaatoy, G. Evin, and C. Selve: Réactifs de couplage peptidique. L’hexafluorophosphate de benzotriazolyl-N-oxytrisdimethyl-aminophosphonium (BOP). Tetrahedron Lett. 14, 1219 (1975).CrossRefGoogle Scholar
  67. 66.
    Wissmann, H., and H.J. Kleiner: Neue Peptidsynthese. Angew. Chem. 92, 129 (1980); Angew. Chem. Int. Ed. Engl. 19, 133 (1980).Google Scholar
  68. 67.
    Kovacs, J.: In: The Peptides, Vol. 2, p. 485. New York: Academic Press. 1980.Google Scholar
  69. 68.
    Wenger, R.M.: Synthesis of Cyclosporine and Analogues: Structure Activity Relationships of New Cyclosporine Derivatives. Transplantation Proceedings, Vol. XV, No. 4, Suppl. 1, 2230 (1983).Google Scholar
  70. 69.
    Seebach, D., W. Murtiasiiaw, R. Naef, S.I. Shoda (ETH Zürich), and M. Krieger, P. Bollinger, A. Leutwiler, and R. Wenger (Sandoz Ltd.): Aktive CyclosporinDerivate durch C-Alkylierung unter Ersatz von H’ der Sarkosin-Einheit. Erzeugung Polythiierter Peptide. Work presented at the autumn session of the Swiss Chemical Society in Berne (October 18, 1985). Manuscript in preparation.Google Scholar
  71. 70.
    Borel, J.F., and B. Ryffel: The Mechanism of Action of Ciclosporin, a Continuing Puzzle. In: Ciclosporin in Autoimmune Diseases, p. 24. Berlin-Heidelberg-New York: Springer. 1985.CrossRefGoogle Scholar
  72. 71.
    Hess, A.D., and P.M. Colombani: Mechanism of Action, in vitro Studies. In: Progress in Allergy, Vol. 38, p. 198. Basel: Karger. 1986.Google Scholar
  73. 72.
    Larson, D.F.: Mechanism of Action, Antagonism of the Prolactin Receptor. In: Progress in Allergy, Vol. 38, p. 222. Basel: Karger. 1986.Google Scholar
  74. 73.
    Hiestand, P.C., and P. Meckler: Mechanism of Action, Ciclosporin-and ProlactinMediated Control of Immunity In Progress in Allergy, Vol. 38, p. 239. Basel: Karger. 1986.Google Scholar
  75. 74.
    Schreier, M.H.: Interleukin-2 and its Role in the Immune System. Triangle 23, 141 (1984).Google Scholar
  76. 75.
    Batchelor, J.R.: Genetic Role in Autoimmunity. In: Ciclosporin in Autoimmune Diseases, p. 24. Berlin-Heidelberg-New York: Springer. 1985.Google Scholar
  77. 76.
    Morgan, D.A., F.W. Ruscetti, and R. Gallo: Selective in vitro Growth of T-Lymphocytes from Normal Human Bone Marrow. Science 193, 1007 (1976).CrossRefGoogle Scholar
  78. 77.
    Bunjes, D., C. Hardt, M. Roellinghoff, and H. Wagner: Cyclosporin A Mediates Immunosuppression of Primary Cytotoxic T Cell Responses by Impairing the Release of Interleukin 1 and Interleukin 2. Europ. J. Immunol. 11, 657 (1981).CrossRefGoogle Scholar
  79. 78.
    Ryffel, B., U. Goetz, and B. Heuberger: Cyclosporin Receptors on Human Lymphocytes. J. Immunol. 129, 1978 (1982).Google Scholar
  80. 79.
    Miyawaki, T., A. Yachie, S. Oxzeki, T. Nagaoki, and N. Taniguchi: Cyclosporin A Does not Prevent Expression of Tac Antigen, a Probable TCGF Receptor Molecule, on Mitogen-Stimulated Human T Cells. J. Immunol. 130, 2737 (1983).Google Scholar
  81. 80.
    Kunkl, A., and G.G.B. Klaus: Selective Effects of Cyclosporin A on Functional B Cell Subsets in the Mouse. J. Immunol. 125, 2526 (1980).Google Scholar
  82. 81.
    Kroenke, M., W.J. Leonhard, J.M. Depper, S.K. Arya, F. Wong-Staal, R.C. Gallo, T.A. Waldmann, and W.C. Greene: Cyclosporin A Inhibits T-Cell Growth Factor Gene Expression at the Level of mRNA Transcription. Proc. Nat. Acad. Sci. USA 81, 5214 (1984).CrossRefGoogle Scholar
  83. 82.
    Handschumacher, R.E., M.W. Hardy, J. Rich, R.J. Drugge, and D.W. Speicher: Cyclosphilin: a Specific Cytosolic Binding Protein for Cyclosporin A. Science 226, 544 (1984).CrossRefGoogle Scholar
  84. 83.
    Harding, M.W., R.E. Handschumacher, and D.W. Speicher: Isolation and Amino Acid Sequence of Cyclophilin J Biol. Chem. 261, 8547 (1986).Google Scholar
  85. 84.
    Colombani, P.M., A. Robb, and A.D. Hess: Cyclosporin A binding to Calmodulin: a Possible Site of Action on T-Lymphocytes. Science 228, 337 (1985).CrossRefGoogle Scholar
  86. 85.
    Hass, A.D., T. Tuszynski, P. Engel, P.M. Colombani, J. Farrington, R. Wenger, and B. Ryffel: Intracellular and Nuclear Localization of Cyclosporine and Peripheral Blood Mononuclear Cells. Transplant. Proc. 18, 861 (1986).Google Scholar
  87. 86.
    Hiestand, P. (Sandoz Basel), A.D. Hass (Baltimore), and R.E. Handschumacher (New Haven): Unpublished Results, personal communication.Google Scholar

Copyright information

© Springer-Verlag/Wien 1986

Authors and Affiliations

  • R. M. Wenger
    • 1
  1. 1.Preclinical ResearchSandoz Ltd.BaselSwitzerland

Personalised recommendations