Thalidomide metabolites and analogues. 3. Synthesis and antiangiogenic activity of the teratogenic and TNFα-modulatory thalidomide analogue 2-(2,6-dioxopiperidine-3-yl)phthalimidine

Journal of Medicinal Chemistry

Volumn 46, Issue 18, 2003, Pages 3793-3799

  Luzzio, Frederick A ^a   Mayorov, Alexander V ^a   Ng, Sylvia S W ^b   Kruger, Erwin A ^b   Figg, William D ^b  

^a UNIVERSITY OF LOUISVILLE   (United States)

^b NATIONAL CANCER INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 (2,6 DIOXOPIPERIDIN 3 YL)PHTHALIMIDINE; ANGIOGENESIS INHIBITOR; THALIDOMIDE DERIVATIVE; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

ARTICLE; BIOASSAY; DESULFURIZATION; DRUG STABILITY; ENDOTHELIUM CELL; HYDROLYSIS; METABOLIC ACTIVATION; METABOLITE; PRIMATE; STRUCTURE ACTIVITY RELATION; SYNTHESIS; TERATOGENESIS;

ANGIOGENESIS INHIBITORS; ANIMALS; AORTA; CULTURE TECHNIQUES; FEMALE; MICROCIRCULATION; MUSCLE, SMOOTH, VASCULAR; RATS; RATS, SPRAGUE-DAWLEY; STRUCTURE-ACTIVITY RELATIONSHIP; THALIDOMIDE; TUMOR NECROSIS FACTOR-ALPHA;

EID: 0042921615     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm020079d     Document Type: Article

References (28)

1. (a) Thalidomide Analogs and Metabolites, Part 3. For Part 2, see the following. Luzzio, F. A.; Thomas, E. M.; Figg, W. D. Tetrahedron Lett. 2000, 41, 7151-7155.
2. (b) Presented at the 222nd National Meeting of the American Chemical Society, Chicago, IL, August 29, 2001; Paper MEDI 0264.
3. Rosen, L. Antiangiogenic Strategies and Agents in Clinical Trials. Oncologist 2000, 5 (Suppl.), 20-27.
4. Helm, F. C.; Frankus, E.; Friderichs, E.; Graudums, I.; Flohé, L. Comparative Teratological Investigation of Compounds Structurally and Pharmacologically Related to Thalidomide Arzneim.-Forsch. 1981, 31, 941-949.
5. (a) Udagawa, T.; Verheul, H. M. W.; D'Amato, R. J. Thalidomide and Analogs. In Antiangiogenic Agents in Cancer Therapy; Teicher, B. A., Ed.; Humana Press: Totowa, NJ, 1999; pp 263-274.
6. (b) Figg, W. D.; Reed, E.; Green, S.; Pluda, J. Thalidomide A Prodrug That Inhibits Angiogenesis. In Antiangiogenic Agents in Cancer Therapy; Teicher, B. A., Ed.; Humana Press: Totowa, NJ, 1999; pp 407-422.
7. Schmahl, H.-J.; Nau, H.; Neubert, D. The Enantiomers of the Teratogenic Thalidomide Analogue EM 12. Arch. Toxicol. 1988, 62, 200-204.
8. Heger, W.; Klug, S.; Schmahl, H.-J.; Nau, H.; Merker, H.-J.; Neubert, D. Embryotoxic Effects of Thalidomide Derivatives on the Non-Human Primate Callithrix jacchus. Arch. Toxicol. 1988, 62, 205-208.
9. Schmahl, H.-J.; Heger, W.; Nau, H. The Enantiomers of the Teratogenic Thalidomide Analogue EM 12. Toxicol. Lett. 1989, 45, 23-33.
10. Winckler, K.; Klinkmüller, K. D.; Schmal, H. J. Determination of the Thalidomide Analogues 2-(2,6-Dioxopiperidine-3-yl) Phthalimidine (EM 12), 2-(2,6-dioxopiperidine-4yl) Phthalimidine (EM 16) and Their Metabolites in Biological Samples. J. Chromatog. Biomed. Appl. 1989, 488, 417-425.
11. Kaplan, G.; Sampaio, E. P. Method of Treating Abnormal Concentrations of TNFα U.S. Patent 5,385,901, 1992 (to Rockefeller University); Chem. Abstr. 1992, 117, 226313a.
12. Shah, J. H.; Swartz, G. M.; Papathanassiu, A. E.; Treston, A. M.; Fogler, W. E.; Madsen, J. W.; Green, S. J. Synthesis and Enantiomeric Separation of 2-Phthalimidinoglutaric Acid Analogues: Potent Inhibitors of Tumor Metastasis. J. Med. Chem. 1999, 42, 3014-3017.
13. Neubert, R.; Nogueira, A. C.; Neubert, D. Thalidomide Derivatives and the Immune System I. Changes in the Pattern of Integrin Receptors and Other Surface Markers on T Lymphocyte Subpopulations of Marmoset Blood. Arch. Toxicol. 1993, 67, 1-17.
14. D'Amato, R. J.; Loughnan, M. S.; Flynn, E.; Folkman, J. Thalidomide is an Inhibitor of Angiogenesis. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 4082-4085.
15. Bauer, K. S.; Dixon, S. C.; Figg, W. D. Inhibition of Angiogenesis by Thalidomide Requires Metabolic Activation Which Is Species-Dependent. Biochem. Pharmacol. 1998, 55, 1827-1834.
16. Hansen, J. M.; Carney, E. W.; Harris, C. Differential Alteration by Thalidomide of the Glutathione Content of Rat vs. Rabbit Conceptuses in Vitro. Reprod. Toxicol. 1999, 13, 547-554.
17. (a) Green, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991; p 400.
18. Although the PMB route to 1 was described in an earlier publication (see ref 17), no experimental details were provided. Full experimental details are provided in this report where the yields in some steps differ because of scale-up.
19. Luzzio, F. A.; Mayorov, A. V.; Figg, W. D. Thalidomide Metabolites. Part I: Derivatives of (+)-2-N-Phthalimido-γ-hydroxyglutamic Acid Tetrahedron Lett. 2000, 41, 2275-228.
20. Luzzio, F. A.; Piatt Zacherl, D. P.; Figg, W. D. A Facile Scheme for Phthalimide/-Phthalimidine Conversion. Tetrahedron Lett. 1999, 40, 2087-2090.
21. Guo, Z.; Schultz, A. G. Organic Synthesis Methodology. Preparation and Diastereoselective Birch Reduction-Alkylation of 3-Substituted 2-Methyl-2,3-Dihydroisoindol-1-ones. J. Org. Chem. 2001, 66, 2154-2157.
22. (a) Benzylamines are not well-suited for glutarimide formation because of their lower nucleophilicity (see ref 20). In contrast, β-phenethylamine gave the corresponding glutarimide in 83% yield using method A.
23. (b) Fox, D. J.; Reckless, J.; Warren, S. J.; Grainger, D. J. Design, Synthesis and Preliminary Pharmacological Evaluation of N-Acyl-3-aminoglutarimides as Broad-Spectrum Chemokine Inhibitors in Vitro and Anti-inflammatory Agents in Vivo. J. Med Chem. 2002, 45, 360-370.
24. Robin, S.; Zhu, J.; Galons, H.; Pham-Huy, C.; Claude, J. R.; Tomas, A.; Viossat, B. A Convenient Asymmetric Synthesis of Thalidomide. Tetrahedron: Asymmetry 1995; 6, 1249-1252. The electron-donating capacity of the NBO group presumably reduces racemization of the product thalidomide.
25. Hart, D. J.; Yang, T.-K. N-Acyliminium Ion Rearrangements: Generalities and Application to the Synthesis of Pyrrolizidine Alkaloids. J. Org. Chem. 1985, 50, 235-242.
26. Nicosia, R. F.; Ottinetti, A. Growth of Microvessels in Serum-Free Matrix Culture of Rat Aorta. Lab. Invest. 1990, 63, 115-122.
27. Hamby, J. M.; Showalter, H. D. H. Small Molecule Inhibitors of Tumor-Promoted Angiogenesis, Including Protein Tyrosine Kinase Inhibitors. Pharmacol. Ther. 1999, 82, 169-193.
28. The NIH Image program was developed at the U.S. National Institutes of Health and is available on the Internet at http://rsb.info.nih.gov/nih-image/.