Synthesis and Immunosuppressive Activity of Novel Succinylacetone Analogues

  • Kim, Taek-Hyeon (Department of Applied Chemistry, College of Engineering, Chonnam National University) ;
  • Oh, Dong-Ryun (Department of Applied Chemistry, College of Engineering, Chonnam National University) ;
  • Na, Hee-Sam (Department of Microbiology, Chonnam National University Medical School) ;
  • Lee, Hyun-Chul (Department of Microbiology, Chonnam National University Medical School)
  • Published : 2003.03.01

Abstract

This study describes the synthesis of novel enol esters (3) and triketones (4) as analogues of succinylacetone (SA) (Ed- this abbreviation is introduced here based on your use of it in the body of the paper) and the evaluation on the mouse allogeneic mixed lymphocyte reaction (MLR) and the murine model of antigen-induced paw edema formation for immunosuppressive activity. Enol esters (3a-f) were about 2-4 fold more potent than SA in in vitro activity.

Keywords

References

  1. Akhrem, A. A., Lakhvich, F. A., Budai, S. I., Khlebnicova, T. S., and Petrusevich, I. I., A new simple synthesis of 2-acylcyclo-hexane-1,3-diones. Synthesis, 925-927 (1978)
  2. Borel, J. F., History of cyclosporin A and its significance in immunology. In cyclosporin A, Borel, J. F., Ed., Elsevier Biochemical Press: Amsterdam, 1982, pp 5-17
  3. Di Pierro, F., dAtri, G., Marcucci, F., and Leoni, F., Use of type I and type IV hypersensitivity responses to define the immuno-pharmacological profile of drugs. J. Pharmacol. Toxicol. Methods, 37, 91-96 (1997) https://doi.org/10.1016/S1056-8719(97)00003-8
  4. Elison, G. B. and Hitchings G. H., Azathioprine. Handb. Exp. Pharmacol., 38, 404-425 (1975)
  5. Fidler, J. M., Chang, T. G., Bauer, R., Young, J. D., and Vitt, C. R., Suppression of graft-versus-host disease by succinylacetone in a rat allogeneic bone marrow transplantation model. Transplantation, 55, 367-373 (1993) https://doi.org/10.1097/00007890-199302000-00026
  6. Hess, R. A., Tschudy, D. P., and Blaese, R. M., Immunosuppression by succinylacetone: II. prevention of graft-vs.-host disease. J. Immunol., 139, 2845-2849 (1987)
  7. Kawai, M., Lane, B. C., Hsieh, G. C., Mollison, K. W., Carter, G. W., and Luly, J. R., FEBS. Lett., 316, 107 (1993) https://doi.org/10.1016/0014-5793(93)81196-7
  8. Lindblad, B., Lindstedt, S., and Steen, G., On the enzyme defects in hereditary tyrosinemia. Proc. Natl. Acad. Sci. USA, 74, 4641-4645 (1977) https://doi.org/10.1073/pnas.74.10.4641
  9. Meo, T., The MLR test in the mouse. In immunological methods, Lefkovits, I., Pernis, B., Eds., Academic Press: New York, 1979, pp 227-239
  10. Montes, I. F. and Burger, U., The cyanide catalyzed isomerisation of enol esters derived from cyclic 1,3-diketones. Tetrahedron Lett., 37, 1007-1010 (1996) https://doi.org/10.1016/0040-4039(95)02362-3
  11. Nitecki, D. E., Moreland, M., Aldwin, L., Levenson, C. H., Braude, I. and Mark, D. F., Preparation of succinylacetone derivatives and analogs as immunosuppressive agents. WO 9000049 (1990)
  12. O'Keefe, S. J. and O'Neill, E. A., Cyclosporin A and FK506: immunosuppression, inhibition of transcription and the role of calcineurin. Perspect. Drug Discovery Des., 2, 85-102 (1994) https://doi.org/10.1007/BF02171738
  13. Perico, N. and Remuzzi, G., Prevention of transplant rejection current treatment guidelines and future developments. Drugs, 54, 533-570 (1997) https://doi.org/10.2165/00003495-199754040-00003
  14. Sanders, S. and Harisdangkul, V. Leflunomide for the treatment of rheumatoid arthritis and autoimmunity. Am. J. Med. Sci., 323, 190-193 (2002) https://doi.org/10.1097/00000441-200204000-00004
  15. Silverman, R. B., The organic chemistry of drug design and drug action. Academic Press, New York, pp. 19-24 (1992)
  16. Shaw, L. M., Kaplan, B. and Kaufman, D., Toxic effects of immunosuppressive drugs: mechanism and strategies for controlling them. Clin. Chem., 42, 1316-1321 (1996)
  17. Skolik, S. A., Palestine, A. G., Blaese, R. M. Nussenblatt, R. B., and Hess, R. A., Treatment of experimental autoimmune uveitis in the rat with systemic succinylacetone. Clin. Immunol. Immunopathol. 49, 63-71 (1988) https://doi.org/10.1016/0090-1229(88)90095-5
  18. Tanaka, H., Kuroda, A., Marusawa, H., Hatanaka, H., Kino, T., Goto, T., Hashimoto, M., and Taga, T., Structure of FK506: a novel immunosuppressant (Ed- confirm the singular) isolated from Streptomyces. J. Am. Chem. Soc., 109, 5031-5033 (1987) https://doi.org/10.1021/ja00250a050
  19. Tang, Q. and Sen, S. E., Carbomethoxypropionyl cyanide: a regioselective C-alkylation reagent for the preparation of $\beta$-dicarbonyl compounds. Tetrahedron Lett., 39, 2249-2252 (1998) https://doi.org/10.1016/S0040-4039(98)00284-6
  20. Tschudy, D. P., Hess, R., Frykholm, B., and Blaese, R. M., Immunosuppressive activity of succinylacetone. J. Lab. Clin. Med., 99, 526-532 (1981)