Structure-activity relationships for inhibition of inosine monophosphate dehydrogenase by nuclear variants of mycophenolic acid

Journal of Medicinal Chemistry

Volumn 39, Issue 21, 1996, Pages 4181-4196

  Nelson, Peter H ^a   Carr, Stephen F ^b   Devens, Bruce H ^b   Eugui, Elsie M ^b   Franco, Fidencio ^c   Gonzalez, Carlos ^c   Hawley, Ronald C ^a   Loughhead, David G ^a,b   Milan, David J ^a   Papp, Eva ^b   Patterson, John W ^a   Rouhafza, Sussan ^b   Sjogren, Eric B ^a   Smith, David B ^a   Stephenson, Rebecca A ^a   Talamas, Francisco X ^c   Waltos, Ann Marie ^a   Weikert, Robert J ^a   Wu, John C ^b  

^a Syntex Research Institute of Organic Chemistry   (United States)

^b ROCHE BIOSCIENCE   (United States)

^c Syntex SA de CV   (Mexico)

Author keywords

[No Author keywords available]

Indexed keywords

DRUG DERIVATIVE; INOSINATE DEHYDROGENASE; LACTONE; MYCOPHENOLIC ACID;

ANIMAL CELL; ARTICLE; DRUG MECHANISM; DRUG POTENCY; ENZYME INHIBITION; FEMALE; HUMAN; HUMAN CELL; LYMPHOCYTE PROLIFERATION; MITOGENESIS; MOUSE; NONHUMAN; ORAL DRUG ADMINISTRATION; STRUCTURE ACTIVITY RELATION;

ANIMALS; CELL DIVISION; FEMALE; HEMOLYTIC PLAQUE TECHNIQUE; HUMANS; IMP DEHYDROGENASE; LYMPHOCYTES; MICE; MICE, INBRED C3H; MYCOPHENOLIC ACID; RECOMBINANT PROTEINS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 10244220030     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9603633     Document Type: Article

References (77)

1. Contribution No. 918 from the Syntex Institute of Organic Chemistry.
2. Clutterbuck, P. W.; Oxford, A. E.; Raistrick, H.; Smith, G. Studies in the Biochemistry of Micro-organisms. XXIV. The Metabolic Products of the Penicillium Brevi-compactum Series. Biochem. J. 1932, 26, 1441-1458.
3. (a) Noto, T.; Sawada, M.; Ando, K.; Koyama, K. Some Biological Properties of Mycophenolic Acid. J. Antibiot. 1969, 22, 165-169.
4. (b) Gallagher, J. A.; Quinn, C. M.; Whittaker, P. A. The action of mycophenolic acid on Candida albicans. Biochem. Soc. Trans. 1987, 15, 290.
5. Abraham, E. P. The Effect of Mycophenolic Acid on the Growth of Staphylococcus aureus in Heart Broth. Biochem. J. 1945, 39, 398-408.
6. (a) Williams, R. H.; Lively, D. H.; DeLong, D. C.; Cline, J. C.; Sweeney, M. J.; Poore, G. A.; Larsen, S. H. Mycophenolic acid: Antiviral and Antitumor Properties. J. Antibiot. 1968, 21, 463-464.
7. (b) Sweeney, M. J.; Cline, J. C.; Williams, R. H. Antitumor and Antiviral Activities of Mycophenolic Acid. Proc. Am. Assoc. Cancer Res. 1969, 10, 90.
8. Mitsui, A.; Suzuki, S. Immunosuppressive Effects of Mycophenolic Acid. J. Antibiot. 1969, 22, 358-363.
9. Knudtzon, S.; Nissen, N. I. Clinical Trial with Mycophenolic Acid (NSC-129185), a new Antitumor Agent. Cancer Chemother. Rep. 1972, 56, 221-227.
10. Epinette, W. W.; Parker, C. M.; Jones, E. L.; Griest, M. C. Mycophenolic acid for psoriasis. J. Am. Acad. Dermatol. 1987, 17, 962-971.
11. Carter, S. B.; Franklin, T. J.; Jones, D. F.; Leonard, B. J.; Mills, S. D.; Turner, R. W.; Turner, W. B. Mycophenolic Acid: an Anti-cancer Compound with Unusual Properties. Nature 1969, 223, 848-850.
12. (a) Natsumeda, Y.; Ohno, S.; Kawasaki, H.; Konno, Y.; Weber, G.; Suzuki, K. Two Distinct cDNA's for Human IMP Dehydrogenase. J. Biol. Chem. 1990, 265, 5292-5295.
13. (b) Konno, Y.; Natsumeda, Y.; Nagai, M.; Yamaji, Y.; Ohno, S.; Suzuki, K.; Weber, G. Expression of Human IMP Dehydrogenase Types I and II in Escherichia coli and Distribution in Human Normal Lymphocytes and Leukemic Cell Lines. J. Biol. Chem. 1991, 266, 506-509.
14. (a) Natsumeda, Y.; Ikegami, T.; Murayama, K.; Weber, G. De Novo Guanylate Synthesis in the Commitment to Replication in Hepatoma 3924A Cells. Cancer Res. 1988, 48, 507-511.
15. (b) Nagai, M.; Natsumeda, Y.; Konno, Y.; Hoffman, R.; Irino, S.; Weber, G. Selective Up-Regulation of Type II Inosine 5′-Monophosphate Dehydrogenase Messenger RNA Expression in Human Leukemias. Cancer Res. 1991, 51, 3886-3890.
16. Allison, A. C.; Eugui, E. M. Immunosuppressive and other Effects of Mycophenolic Acid and an Ester Prodrug, Mycophenolate Mofetil. Immunol. Rev. 1993, 136, 5-28.
17. Lee, W. A.; Gu, L.; Miksztal, A. R.; Chu, N.; Leung, K.; Nelson, P. H. Bioavailability Improvement of Mycophenolic Acid Through Amino Ester Derivatization. Pharm. Res. 1990, 7, 161-166.
18. Goldblum, R. Therapy of rheumatoid arthritis with mycophenolate mofetil. Clin. Exp. Rheumatol. 1993, 11 (Suppl. 8), S117-S119.
19. (a) Deierhoi, M. H.; Kauffman, R. S.; Hudson, S. L.; Barber, W. H.; Curtis, J. J.; Julian, B. A.; Gaston, R. S.; Laskow, D. A.; Diethelm, A. G. Experience with Mycophenolate Mofetil (RS61443) in Renal Transplantation at a Single Center. Ann. Surg. 1993, 277, 476-484.
20. (b) Ensley, R. D.; Bristow, M. R.; Olsen, S. L.; Taylor, D. O.; Hammond, E. H.; O'Connell, J. B.; Dunn, D.; Osburn, L.; Jones, K. W.; Kaufmann, R. S.; et al. The use of mycophenolate mofetil (RS-61443) in human heart transplant recipients. Transplantation 1993, 56, 75-82.
21. (c) Taylor, D. O.; Ensley, R. D.; Olsen, S. L.; Dunn, D.; Renlund, D. G. Mycophenolate Mofetil (RS-61443): Preclinical, Clinical and Three-year Experience in Heart Transplantation. J. Heart Lung Transplant. 1994, 13, 571-582.
22. Nelson, P. H.; Eugui, E.; Wang, C. C.; Allison, A. C. Synthesis and Immunosuppressive Activity of Some Side-Chain Variants of Mycophenolic Acid. J. Med. Chem. 1990, 33, 833-838.
23. Ohsugi, Y.; Suzuki, S.; Takagaki, Y. Antitumor and Immunosuppressive Effects of Mycophenolic Acid Derivatives. Cancer Res. 1976, 36, 2923-2927.
24. (a) Sweeney, M. J.; Hoffman, D. H.; Poore, G. A. Possible in Situ Activation of Mycophenolic Acid by β-Glucuronidase. Cancer Res. 1971, 31, 477-478.
25. (b) Sweeney, M. J.; Hoffman, D. H.; Esterman, M. E. Metabolism and Biochemistry of Mycophenolic Acid. Cancer Res. 1972, 32, 1803-1809.
26. (c) Matsuzawa, Y.; Nakase, T. Metabolic fate of ethyl O-[N-(p-carboxyphenyl)-carbamoyl]mycophenolate (CAM), a new antitumor agent, in experimental animals. J. Pharmacobio-Dyn. 1984, 7, 776-783.
27. (a) Canonica, L.; Rindone, B.; Santaniello, E.; Scolastico, C. A Total Synthesis of Mycophenolic Acid, Some Analogues and Some Biogenetic Intermediates. Tetrahedron 1972, 28, 4395-4404.
28. (b) Jones, D. F.; Mills, S. D. Preparation and Antitumor Properties of Analogs and Derivatives of Mycophenolic Acid. J. Med. Chem. 1971, 14, 305-311.
29. (c) Lee, J.; Anderson, W. K. A Facile Synthesis of an (E)-4-Methyl-4-hexenoic Acid Substituted Pyridine Analogue of Mycophenolic Acid. Synth. Commun. 1992, 22, 369-376.
30. (d) Beisler, J. A.; Hillery, S. S. Antitumor Agents II: Nitrogen Analogs of Mycophenolic Acid. J. Pharm. Sci. 1975, 64, 84-87.
31. (e) Jones, D. F.; Moore, R. H.; Crawley, G. C. Microbial Modification of Mycophenolic Acid. J. Chem. Soc. C 1970, 1725-1737.
32. 2O Catalysed Amino-Claisen Rearrangement. Tetrahedron Let. 1993, 34, 6849-6852.
33. (g) Anderson, W. K.; Boehm, T. L.; Makara, G. M.; Swann, R. T. Synthesis and Modeling Studies with Monocyclic Analogues of Mycophenolic Acid. J. Med. Chem. 1996, 39, 46-55.
34. Patterson, J. W.; Huang, G. T. The Orthoester Claisen Rearrangement in the Synthesis of Mycophenolic Acid. J. Chem. Soc., Chem. Commun. 1991, 1579-1580.
35. Clark, R. D.; Muchowski, J. M.; Souchet, M.; Repke, D. B. Synthesis of Protected Indoles from N-tert-Butoxycarbonyl-2-alkylanilines. Synlett 1990, 207-208.
36. Carr, S. F.; Papp, E.; Wu, J. C.; Natsumeda, Y. Characterization of Human Type I and Type II IMP Dehydrogenaaes. J. Biol. Chem. 1993, 268, 27286-27290.
37. Sweeney, M. J.; Gerzon, K.; Harris, P. N.; Holmes, R. E.; Poore, G. A.; Williams, R. H. Experimental Antitumor Activity and Preclinical Toxicology of Mycophenolic Acid. Cancer Res. 1972, 32, 1795-1802.
38. Molar refractivity values were used to compare the size of substituents. Kubinyi, H. QSAR: Hansch Analysis and Related Approaches; VCH: New York, 1993; pp 21-27.
39. Sjogren, E. B. Unpublished results from these laboratories, 1990. See also: Sjogren, E. B. 4-Amino Derivatives of Mycophenolic Acid. U.S. Patent 5,441,953, 1995.
40. Sjogren, E. B. Unpublished results from these laboratories, 1990. See also: Sjogren, E. B. 4-Amino Derivatives of Mycophenolic Acid. U.S. Patent 5,441,953, 1995.
41. Or, Y. S.; Liu, L.; Lane, B.; Hsieh, G.; Sweeney, D.; Mollison, K. W.; Luly, J. R. Design and synthesis of mycophenolic acid analogs as potential immunosuppressants. Division of Medicinal Chemistry, 208th National Meeting of the American Chemical Society, Washington, DC, August 1994; Poster 112.
42. Jerne, N. K.; Henry, C.; Nordin, A. A.; Fuji, H.; Koros, A. M. C.; Lefkovits, I. Plaque forming cells: Methodology and theory. Transplant. Rev. 1974, 18, 130-191.
43. Appreciably higher yields were obtained if the ortho-ester was distilled immediately prior to use.
44. Both the silyl ether and methyl ester groups could be removed in one step, using LiOH in 1:1 aqueous glyme at 60 °C for 2-4 h.
45. 2), 5.15-5.35 (t, J = ∼7 Hz, =CH).
46. Liotta, D.; Saindane, M.; Barnum, C.; Zima, G. Synthetic Applications of 2-Phenylselenylenones-III. An Overview. Tetrahedron 1985, 41, 4881-4889.
47. Watanabe, M.; Tsukazaki, M.; Hamada, Y.; Iwao, M.; Furukawa, S. An Efficient Synthesis of Phthalides by Diels-Alder Reaction of Sulphur-Substituted Furanones with Silyloxydienes: a Formal Synthesis of Mycophenolic Acid. Chem. Pharm. Bull. 1989, 37, 2948-2951.
48. The product was obtained as a 3.5:1.5:1 mixture of isomers. The loss of the phenylselenyl group was unexpected.
49. Kato, M.; Ouchi, A.; Yoshikoshi, A. A Useful Synthetic Method for 3-Substituted δ-Lactones. Synthesis of (±)-Secocrispiolide. Bull. Chem. Soc. Jpn. 1991, 64, 1479-1486.
50. Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G. Palladium-Catalysed Carbonylation of Aryl Triflates. Synthesis of Arenecarboxylic Acid Derivatives from Phenols. Tetrahedron Lett. 1986, 27, 3931-3934.
51. Schmitt, G.; An, N. D.; Poupelin, J.-P.; Vebrel, J.; Laude, B. A New and Mild Synthesis of Substituted Salicylic Acids. Synthesis 1984, 758-760.
52. Birch, A. J.; Wright, J. J. A Total Synthesis of Mycophenolic Acid. Aust. J. Chem. 1969, 22, 2635-2644.
53. Patterson, J. W. The Synthesis of Mycophenolic Acid. Tetrahedron 1993, 49, 4789-4798.
54. A synthesis of this compound in which Penicillium brevicompactum was used to attach the side chain to the nucleus has been reported; see: Canonica, L.; Rindone, B.; Scolastico, C.; Aragozzini, F.; Craveri, R. Halogenated Analogues of Mycophenolic Acid. J. Chem. Soc., Chem. Commun. 1973, 222-223.
55. Intermediate in the preparation of 1r, structure presented in Scheme 6.
56. 14C-Labelled Precursors. J. Chem. Soc., Perkin Trans. 1 1988, 755-761.
57. 13C heteronuclear NMR correlation experiment.
58. 2 for 30 min.
59. The phenolic acetate was removed during the cyanation reaction, and the resultant p-cyanophenol was soluble in aqueous KCN.
60. A lower-yielding preparation of this compound is described in ref 19b.
61. Nelson, P. H.; Nelson, J. T. Synthesis of Tetra- and Pentasubstituted Benzenes from Dimedone and Derivatives. Synthesis 1992, 1287-1291.
62. Attempted preparation of this compound by Claisen rearrangement of the appropriate allyl ether yielded a complex mixture. The following four-step procedure was therefore used.
63. Made by analogy to a published process for aromatization of dimedone derivatives, ref 46.
64. Mori, K.; Sato, K. A General Synthetic Method for Prenylated Phenols of Microbial Origin. Synthesis of Colletochlorins A and B. Tetrahedron 1982, 38, 1221-1225.
65. Burnell, R. H.; Ringuet, M. Synthesis of dehydrocycloroyleanone. Can. J. Chem. 1978, 56, 517-521.
66. The methylthio group was introduced by lithiation, followed by reaction with dimethyl disulfide, of the silyl-protected allylic carbinol intermediate in the preparation of 3b.
67. Greenhalgh, R. P. Selective Oxidation of Phenyl Sulphides or Sulphoxides or Sulphones Using Oxone® and Wet Alumina. Synlett 1992, 235-236.
68. (a) Crossley, A. W. Derivatives of o-Xylene. Part VI. 5-Bromo-o-3-xylenol. J. Chem. Soc. 1913, 2179-2182.
69. (b) Alexsandrov, I. V.; Abradushkin, Y. S. Derivatives of 3-Aminophenol I. N-Arylsulfonyl and N-Benzoyl Derivatives of 3-Aminophenol and Its Homologs. J. Gen. Chem. USSR (Engl. Transl.) 1960, 30, 3374-3379
70. Banks, R. E.; Mohialdin-Khaffaf, S. N.; Lal, G. S.; Sharif, I.; Syvret, R. G. 1-Alkyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane Salts: a Novel Family of Electrophilic Fluorinating Agents. J. Chem. Soc., Chem. Commun. 1992, 595-596.
71. The structure of the product was determined by one- and two-dimensional NMR spectroscopy. One- and three-bond shift-correlation spectroscopy was used to establish H-C and H-C-C connectivity, and NOE difference methods were used to identify adjacent substituents on the aromatic ring.
72. Prepared by dehydrogenationof 2,3,4,5-tetramethylnitrobenzene; see: Olah, G. A.; Lin, H. C. Synthetic Methods and Reactions; VI. Boron Trifluoride Catalyzed Mononitration of Tetramethylbenzenes and Pentamethylbenzene with Methyl Nitrate in Nitromethane Solution. A New Selective Nitration Method. Synthesis 1973, 488-490.
73. Kajigaeshi, S.; Kakinami, T.; Tokiyama, H.; Hirakawa, T.; Okamoto, T. Bromination of Phenols by Use of Benzyltrimethylammonium Tribromide. Chem. Lett. 1987, 627-630.
74. Cortese, N. A.; Heck, R. F. Palladium-Catalyzed Reductions of Halo- and Nitroaromatic Compounds with Triethylammonium Formate. J. Org. Chem. 1977, 42, 3491-3494.
75. Eugui, E. M.; Almquist, S. J.; Muller, C. D.; Allison, A. C. Lymphocyte-Selective Cytostatic and Immunosuppressive Effects of Mycophenolic Acid in Vitro: Role of Deoxyguanosine Nucleotide Depletion. Scand. J. Immunol. 1991, 33, 161-173.
76. (a) Jerne, N. K.; Nordin, A. A.; Henry, C. The Agar Plaque Technique for Recognizing Antibody-producing Cells. In Cell-bound Antibodies; Amos, B., Koprowski, H., Eds.; Wistar Institute Press: Philadelphia, 1963; pp 109-125.
77. (b) Mishell, R. I.; Dutton, R. W. Immunization of Normal Mouse Spleen Cell Suspensions in Vitro. Science 1966, 153, 1004-1006.