Structure-immunosuppressive activity relationships of new analogues of 15-deoxyspergualin. 1. Structural modifications of the hydroxyglycine moiety

Journal of Medicinal Chemistry

Volumn 42, Issue 2, 1999, Pages 277-290

  Lebreton, Luc ^a   Annat, Jocelyne ^a   Derrepas, Philippe ^a   Dutartre, Patrick ^a   Renaut, Patrice ^a  

^a Laboratoires Fournier SA   (France)

Author keywords

[No Author keywords available]

Indexed keywords

15 DEOXYSPERGUALIN; 4 [3 (AMINOPROPYL)AMINO]BUTYLCARBAMIC ACID, 2 [[6 [(AMINOIMINOMETHYL)AMINO]HEXYL]AMINO] 2 OXOETHYL ESTER, TRIS(TRIFLUOROACETATE); IMMUNOSUPPRESSIVE AGENT; N [4 [[3 (AMINO)PROPYL]AMINO]BUTYL] N' [[[[6 [(AMINOIMINOMETHYL)AMINO]HEXYL]AMINO]CARBONYL]METHYL]PROPANEDIAMIDE, TRIS(TRIFLUOROACETATE); UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CONFORMATIONAL TRANSITION; DRUG CONFORMATION; DRUG EFFECT; DRUG POTENCY; GRAFT VERSUS HOST REACTION; HEART TRANSPLANTATION; IMMUNOREGULATION; IMMUNOSUPPRESSIVE TREATMENT; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION;

ANIMALS; GLYCINE; GRAFT VS HOST DISEASE; GUANIDINES; HEART TRANSPLANTATION; IMMUNOSUPPRESSIVE AGENTS; MAGNETIC RESONANCE SPECTROSCOPY; MICE; MOLECULAR STRUCTURE; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; TRANSPLANTATION, HOMOLOGOUS;

EID: 0032931738     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm980431g     Document Type: Article

References (43)

1. Elion, G. B.; Hitchings G. H. Azathioprine. Handb. Exp. Pharmacol. 1975, 38/2, 404-425.
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. (a) Tanaka, H.; Kuroda, A.; Marusawa, H.; Hatanaka, H.; Kino, T.; Goto, T.; Hashimoto, M.; Taga, T. Structure of FK506: A Novel Immunosuppressant Isolated from Streptomyces. J. Am. Chem. Soc. 1987, 709, 5031-5033.
4. (b) Parsons, W. H.; Sigal, N. H.; Wyvratt, M. J. FK506, a Novel Immunosuppressant. Ann. N.Y. Acad. Sci. (United States) 1993, 685 (June 23), 22-36.
5. (a) O'Keefe, S. J.; O'Neill, E. A. Cyclosporin A and FK506: Immunosuppression, Inhibition of Transcription and the Role of Calcineurin. Perspect. Drug Discovery Des. 1994, 2, 85-102.
6. (b) Wiederrecht, G.; Lam, E.; Hung, S.; Martin, M.; Sigal, N. The Mechanism of Action of FK506 and Cyclosporin A. Ann. N.Y. Acad. Sci. (United State) 1993, 696 (November 30), 9-19.
7. (a) Eugui, E. M.; Allison, A. C. Immunosuppressive Activity of Mycophenolate Mofetil. Ann. N.Y. Acad. Sci. (United States) 1993, 685 (June 23), 309-329.
8. (a) Shaw, L. M.; Kaplan, B.; Kaufman, D. Toxic effects of immunosuppressive drugs: mechanism and strategies for controlling them. Clin. Chem. 1996, 42:8(B), 1316-1321.
9. (b) Perico, N.; Remuzzi, G. Prevention of Transplant Rejection Current Treatment Guidelines and Future Developments. Drugs 1997, 54 (4), 533-570.
10. Maeda, K.; Umeda, Y.; Saino, T. Synthesis and Background Chemistry of 15-Deoxyspergualin. Ann. N.Y. Acad. Sci. (United States) 1993, 685 (June 23), 123-135 and references cited therein.
11. (a) Nadler, S. G.; Tepper, M. A.; Schacter B.; Mazzucco C. Interaction of the Immunosuppressant Deoxyspergualin with a Member of the Hsp 70 Family of Heat Shock Proteins. Science 1992, 258 (October 16), 484-486.
12. (b) Tepper, M. A.; Nadler, S.; Mazzucco, C.; Singh, C.; Kelley, S. L. 15-Deoxyspergualin, a Novel Immunosuppressive Drug: Studies of the Mechanism of Action. Ann. N.Y. Acad. Sci. (United States) 1993, 685 (June 23), 136-147.
13. (c) Mazzucco, C. E.; Nadler, S. G.; A Member of the HSP70 Family of Heat-Shock Protein is a Putative Target for the Immunosuppressant 15-Deoxyspergualin. Ann. N.Y. Acad. Sci. (United States) 1993, 685 (June 23), 202-204.
14. (d) Amemiya, H. Discovery, Rationale and Clinical Status of 15-Deoxyspergualin (DSG). In Principles of Drug Development in Transplantation and Autoimmunity; Lieberman, R., Mukherjee, A., Eds.; R. G. Landes Company: Austin, TX, 1996.
15. Takeuchi, T.; Iinuma, H.; Kunimoto, S.; Masuda, T.; Ishizuka, M.; Takeuchi, M.; Hamada, M.; Naganawa, H.; Kondo, S.; Umezawa, H. A New Antitumor Antibiotic, Spergualin: Isolation and Antitumor Activity. J. Antibiot. 1981, 34, 1619-1621.
16. Iwasawa, H.; Kondo, S.; Ikeda, D.; Takeuchi, T.; Umezawa, H. Synthesis of (-)15-Deoxyspergualin and (-)Spergualin-15-phosphate. J. Antibiot. 1982, 35, 1655-1669.
17. Umeda, Y.; Moriguchi, M.; Ikai, K.; Kuroda, H.; Nakaruma, T.; Fujii, A.; Takeuchi, T.; Umezawa, H. Synthesis and Antitumor Activity of Spergualin Analogues. III Novel Method for Synthesis of Optically Active 15-Deoxyspergualin and 15-Deoxy-11-O-methylspergualin. J. Antibiot. 1987, 40, 1316-1324.
18. The Umezawa's synthesis of (-)DSG described in ref 11 involves a nine-step process with 0.3% overall yield. As part of our program, we needed a more efficient synthesis of (-)DSG and derivatives which will be published very soon: Durand, P.; Richard, P.; Renaut, P. (-)15-Deoxyspergualin: A New and Efficient Enantioselective Synthesis which allows the Definitive Assignment of the Absolute Configuration. J. Org. Chem. In press.
19. Umezawa, H.; Takeuchi, T.; Kondo, S.; Linuma, H.; Ikeda, D.; Nakamura, T.; Fujii, A. French Patent FR 2 514 350.
20. Umeda, Y.; Moriguchi, M.; Kuroda, H.; Nakamura, T.; Iinuma, H.; Takeuchi, T.; Umezawa, H. Synthesis and Antitumor Activity of Spergualin Analogues. I Chemical Modification of 7-Guanidino 3-hydroxyacyl Moiety. J. Antibiot. 1985, 38, 886-898.
21. (a) Masuda, T.; Mizutani, S.; Iijima, M.; Odai, H.; Suda, H.; Ishizuka, M.; Takeuchi, T.; Umezawa, H. Immunosuppressive Activity of 15-Deoxyspergualin and its Effect on Skin Allografts in Rats. J. Antibiot. 1987, 40, 1612-1618.
22. (b) Walter, P.; Dickneite, G.; Feifel, G.; Thies, J. Deoxyspergualin Induces Tolerance in Allogenic Kidney Transplantation. Transplant. Proc. 1987, 19, 3980-3981.
23. (a) Hsu, S.; Thomas, J. M.; Thomas, F. T. Synergism of FK506, DSG and Rabbit Antithymocyte Globulin in Prolongation of Xenografts. Surg. Forum. 1988, 23, 375-377.
24. (b) Demasi, D.; Araneda, D.; Gross, U.; Daniel, H.; Thomas, F. T. 15-Deoxyspergualin is a Potent Immunosuppressive Agent in Xenografting. Eur. Surg. Res. 1988, 20, 167.
25. (c) Kaufman, D. B. Experience with DSG in Experimental Models of Transplantation. In Principles of Drug Development in Transplantation and Autoimmunity; Lieberman, R., Mukherjee, A., Eds.; R. G. Landes Company: Austin, TX, 1996.
26. Nemoto, K.; Ito, J.; Hayashi, M.; Abe, F.; Ohtaka, Y.; Nakamura, T.; Takeuchi, T.; Umezawa, H. Effects of Spergualin and 15-Deoxyspergualin on the Development of Graft-Versus-Host Disease in Mice. Transplant. Proc. 1987, XIX (4), 3520-3521.
27. (a) Nemoto, K; Haiyashi, K.; Sugawara, Y.; Ito, J. Biologic Activities of Deoxyspergualin in Autoimmune Disease Mice. J. Antibiot. 1988, 41, 1253-1257.
28. (b) Schorlemmer, H. U.; Dickneite, G. Preclinical Studies with 15-Deoxyspergualin in Various Animal Models for Autoimmune Diseases. Ann. N.Y. Acad. Sci. (United States) 1993, 685 (June 23), 155-174.
29. (a) Amemiya, H.; Suzuki, S.; Ota, K.; Takahashi, K.; Sonoda, T.; Ishibashi, M.; Omoto, R.; Koyama, I.; Dohi, K.; Fukyda, Y.; Fukao, K. A novel Rescue Drug, 15-Deoxyspergualin. Transplantation 1990, 49 (2), 337-343.
30. (b) SCRIP No. 1884/85, December 24th/28th 1993, p 23.
31. Thomas, F. T.; Tepper, M. A.; Thomas, J. M.; Haish, C. E. 15-Deoxyspergualin: A Novel Immunosuppressive Drug with Clinical Potential. Ann. N.Y. Acad. Sci. (United States) 1993, 685 (June 23), 175-192.
32. Nishizawa, R.; Takei, Y.; Yoshida, M.; Tomiyashi, T.; Saino, T.; Nishikawa, K.; Nemoto, K.; Takahashi, K.; Fujii, A.; Nakamura, T.; Takita, T.; Takeuchi, T. Synthesis and biological activity of spergualin analogues. I. J. Antibiot. 1988, 41, 1629-1643.
33. Bergeron, J. R.; Garlich, J. R.; Stolowich, N. J. Reagents for the Stepwise Functionalization of Spermidine, Homospermidine, and Bis(3-aminopropyl)amine. J. Org. Chem. 1984, 49, 2997-3001.
34. Bergeron, J. R.; McManis, J. Total Synthesis of (±)-15-Deoxyspergualin. J. Org. Chem. 1987, 52, 1700-1703.
35. Pickel, K.; Hoffman, M. K. Suppressor T cells aiming in Mice undergoing Graft Versus Host Response. J. Immunol. 1977, 118, 653-656.
36. 19a has been tested in a heart allotransplantation model (Dark Agouti to Lewis rat combination). Mean graft survival in vehicle treated animals was 7 days. A 6 mg/kg/day i.p. treatment during 10 days starting 1 day after surgery delayed rejection to 12 days. When dosage was increased to 15 mg/kg/day i.p., mortality occurred between day 4 and 6 postsurgery. In contrast, 23 and 27a were well tolerated up to 15 mg/kg during 10 days of treatment and induced an increase of the mean graft survival over 60 days.
37. Klempnauer, J.; Steiniger, B.; Lÿck, R.; Gÿnther, E. Genetic Control of Rat Heart Allograft Rejection: Effect of Different MHC and non MHC Uncompatibilities. Immunogenetics 1989, 30, 81.
38. Westra, A. L.; Petersen, A. H.; Wildevarr, C. R. H.; Brop, P. Factors determining Prolongation of Rat Heart Allografts Survival by perioperative Injection of donor Spleen Cells. Transplantation 1991, 52, 606.
39. Dutartre, P.; Annat, J.; Derrepas, P. LF08-0299 Induces Tolerance After Short Term Treatment in a Fully Major Histocompatibility Mismatched Rat Cardiac Allograft Model. Transplant. Proc. 1995, 27, 440-442.
40. Andoins, C.; De Fornel, D.; Annat, J.; Dutartre, P. Tolerance in a Rat Cardiac Allograft Model after Short-term Treatment with LF 08-0299. Transplantation 1996, 62 (11), 1543-1549.
41. Annat, J.; Churaqui, E.; Dutartre, P.; Bruley-Rosset, M. Prevention of Lethal Graft-versus-host Disease following Allogeneic Bone Marrow Transplantation in Mice by Short Course Administration of LF 08-0299. Transplantation 1996, 62 (6), 721-729.
42. 1,4-Di(p-cumaroyl)spermin, einem möglichen Biogenese-Vorläufer von Aphelandrin. Helv. Chim. Acta 1991, 74, 654-661.
43. Ono, K.; Lindsey, E. S. Improved Technique of Heart Transplantation in Rats. Thorac. Cardiovasc. Surg. 1969, 57, 225.