2,6,9-Trisubstituted purines: Optimization towards highly potent and selective CDK1 inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 9, Issue 1, 1999, Pages 91-96

  Imbach, Patricia ^a   Capraro, Hans Georg ^a   Furet, Pascal ^a   Mett, Helmut ^a   Meyer, Thomas ^a   Zimmermann, Jürg ^a  

^a NOVARTIS PHARMA AG   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

BUTYROLACTONE 1; CYCLIN DEPENDENT KINASE INHIBITOR; FLAVOPIRIDOL; OLOMOUCINE; PURINE DERIVATIVE; STAUROSPORINE; UNCLASSIFIED DRUG;

ANTINEOPLASTIC ACTIVITY; ARTICLE; CELL DIVISION; DRUG POTENCY; DRUG SELECTIVITY; DRUG SPECIFICITY; DRUG TOLERABILITY; ENZYME INHIBITION; ENZYME PURIFICATION; HUMAN; HUMAN CELL; STRUCTURE ACTIVITY RELATION;

ANTINEOPLASTIC AGENTS; CDC2 PROTEIN KINASE; CYCLIC AMP-DEPENDENT PROTEIN KINASES; ENZYME INHIBITORS; EPIDERMAL GROWTH FACTOR; HUMANS; ISOENZYMES; KINETIN; PROTEIN KINASE C; PROTEIN KINASE C-ALPHA; PURINES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0032918488     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(98)00691-X     Document Type: Article

References (34)

1. Norbury, C. and Nurse, P. Annu. Rev. Biochem. 1992, 61, 411-470.
2. Fang, F. and Newport, J.W. Cell 1991, 66, 731-742.
3. Hunt, T. Curr. Opin. Cell Biol. 1989, 1, 274-286.
4. Desai, D.; Gu, Y.; Morgan, D. O.; Mol. Biol. Cell, 1992, 3, 571-582.
5. Gu, Y.; Rosenblatt J.; Morgan, D. O. EMBO J. 1992, 11, 3995-4005.
6. Richardson, H. E.; Stueland, C.S.; Thomas, J,: Russel, P.; Reed, S. I. Genes Dev. 1990, 4, 1332-1344.
7. Serrano, M.; Hannon, G. J.; Beach, D. Nature (London), 1993, 366, 704-707.
8. Gu, Y.; Turck, C. W.; Morgan, D. O.; Nature (London), 1993, 566, 707-710.
9. Rialet, V.; Meijer, L. Anticanc. Res. 1991, 1581-1590.
10. Gadbois, D. M., Hamaguchi, J. R.; Swank, R. A.; Bradbury, E. M. Biochem. Biophys. Res. Comm. 1992, 184, 80-85.
11. Losiewicz, M. D.; Carlson, B. A.; Gurmeet, K.; Sausville, E. A.; Worland. P. Biochem. Biophys.Res.Comm. 1994, 201, 589-595.
12. Kitagawa, M.; Okabe, T.; Oginio, H.; Matsumoto, H.; Suzuki-Takahashi, I.; Kokubo, T.; Higashi, H.; Saitoh, S.; Taya, Y.; Yasuda, H.; Ohba, Y.; Nishimura, S.; Tanaka, N.; Okuyama, A. Oncogene 1993, 8, 2425-2432
13. Vesely, J.; Havlicek, L.; Strnad, M.; Blow, J. J.; Donella-Deana, A.; Pinna, L.; Letham, D. S.; Kato, J.; Lénaik, D.; Leclerc, S.; Meijer, L. Eur. J. Biochem. 1994, 224, 771-786.
14. Meijer, L.; Borgne, A.; Mulner, O.; Chong, J. P.; Blow, J. J.; Inagaki, N.; Inagaki, M.; Delcros, J.-G.; Moulinoux, J.-P. Eur. J. Biochem. 1997, 224, 527-536.
15. DeBondt, H. L.; Rosenblatt, J.; Jancarik, J.; Jones, H. D.; Morgan, D. O.; Kim, S.-H. Nature 1993, 563, 595-602.
16. a) De Azevedo F. W., Jr., W.; Mueller-Dieckmann, H.J; Schulze-Gahmen, U.; Worland, P.J.; Sausville, E.; Kim, S-H. PNAS 1996, 93, 2735-2740.
17. b) Schulze-Gahmen, U.; Brandsen, J.; Jones, H. D.; Morgan, D.O.; Meijer, L.; Vesely, J.; Kim, S-H. Proteins : Struct. Fund. Genet. 1995, 22, 378-391.
18. Furet, P. manuscript in preparation.
19. Norman, T. C.; Gray, N. S.; Koh, J. T.; Schultz, P. G. J. Am. Chem. Soc. 1996, 118, 7430-7431.
20. Nugiel, D. A.; Cornelius, L. A. M.; Corbett, J. W. J. Org. Chem. 1997, 62, 201-203.
21. Gray, N. S.; Kwon, S.; Schultz, P. G. Tetrahedron Lett. 1997, 38 (7), 1161-1164.
22. Schow, S. R.; Mackman, R. L.; Blum, C. L.; Brooks, E.; Horsma, A. G.; Joly, A.; Kerwar, S. S.; Lee, G.; Shiffman, D.; Nelson, M. G.; Wang, X.; Wick, M. M.; Zhang, X.; Lum, R. T. Bioorg. Med.Chem. Lett. 1997, 7, 2697-2702.
23. Fiorini, M. T.; Abell, C. Tetrahedron Lett. 1998, 39, 1827-1830
24. Legraverend, M.; Ludwig, O.; Bisagni, E.; Leclerc, S.; Meijer, L. Bioorg. Med.Chem. Lett. 1998, 8, 793-798.
25. Kjellberg, J.; Johansson, N. G. Nucleosides & Nucleotides 1989, 8(2), 225-256.
26. 1H-NMR, IR, mp if available. Most compounds are also characterized by elem. analysis (C,H,N) or HRMS.
27. Havlicek, L.; Hanus, J.; Vesely, J.; Leclerc, S.; Meijer, L., Shaw, G.; Strnad, M. J. Med. Chem. 1997, 40, 408-412.
28. Arion, D.; Meijer, L.; Brizuela, L. and Beach, D. Cell 1988, 55, 371-378.
29. Rialet, V. and Meijer, L. Anticancer Res. 1991, 11, 1581-1590.
30. Azzi, L.; Meijer, L.; Reed, S.I.; Pidikiti, R. and Tung, H.Y.L. Eur. J. Biochem 1992, 203, 353-360.
31. Meijer, L.; Arion, D.; Golsteyn, R.; Pines, J.; Brizuela, L.; Hunt, T.; and Beach, D. EMBO J. 1989, 8, 2275-2282.
32. Meijer, L.; Azzi, L.; and Wang, J.Y.J. EMBO J. 1991, 8, 2275-2282.
33. Human bladder carcinoma T24 cells Unes obtained from the American Type Culture Collection (ATCC, Rockville, MD, USA) were cultured according the protocol of the manufacturer, passaged twice a week and used from passages 54-74. Cells were seeded at 1.5 × 103 cells/well into 96-well microtiter plates and incubated overnight (16-18h) to allow cells to attach. Adherent cells were washed once with serum-free medium and exposed to serial dilutions of the drugs for 4-5 days. This allowed untreated control cultures to undergo at least 2-3 cell divisions. Individual drug concentrations were assayed in duplicates. After incubation, the cells were fixed with 3.3 % v/v glutaraldehyde, washed with water and stained with 0.05 % methylene blue. After washing, the dye was eluted with 3 % v/v HCl and the optical density measured at 665nm SpectraMax 340 (Bucher, Basel, Switzerland). IC50's were determined by a computerized system (SoftPro) using the formula (OD test - OD start) / (OD control - OD start) × 100. IC50 was defined as the drag concentration which leads to 50 % of cells per well compared to control cultures (100%) at the end of incubation period.
34. Andrejauskas-Buchdunger, E.; Regenass, U. Cancer Res. 1992, 52, 5353-5358.