Paullones, a series of cyclin-dependent kinase inhibitors: Synthesis, evaluation of CDK1/cyclin B inhibition, and in vitro antitumor activity

Journal of Medicinal Chemistry

Volumn 42, Issue 15, 1999, Pages 2909-2919

  Schultz, Christiane ^a   Link, Andreas ^a   Leost, Maryse ^b   Zaharevitz, Daniel W ^c   Gussio, Rick ^c   Sausville, Edward A ^c   Meijer, Laurent ^b   Kunick, Conrad ^a  

^a UNIVERSITY OF HAMBURG   (Germany)

^b STATION BIOLOGIQUE   (France)

^c NATIONAL CANCER INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2,3 DIMETHOXY 9 (TRIFLUOROMETHYL) 7,12 DIHYDROINDOLO[3,2 D][1]BENZAZEPIN 6(5H) ONE; 9 BROMO 2,3 DIMETHOXY 7,12 DIHYDROINDOLO[3,2 D][1]BENZAZEPIN 6(5H) ONE; 9 BROMO 6 (METHYLTHIO) 7,12 DIHYDROINDOLO[3,2 D][1]BENZAZEPINE; ALSTERPAULLONE; ANTINEOPLASTIC AGENT; CYCLIN B; CYCLIN DEPENDENT KINASE INHIBITOR; PAULLONE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL CELL; ANTINEOPLASTIC ACTIVITY; ARTICLE; ASTERIAS; CANCER CELL CULTURE; CONCENTRATION RESPONSE; CONTROLLED STUDY; DRUG CYTOTOXICITY; DRUG POTENCY; DRUG SYNTHESIS; ENZYME INHIBITOR INTERACTION; HUMAN; HUMAN CELL; NONHUMAN; OOCYTE; STRUCTURE ACTIVITY RELATION;

EID: 0033614949     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9900570     Document Type: Article

References (46)

1. Morgan, D. Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu. Rev. Cell Dev. Biol. 1997, 13, 261-291.
2. Draetta, G.; Pagano, M. Cell cycle control and cancer. Annu. Rep. Med. Chem. 1996, 31, 241-248.
3. Hartwell, L. H.; Kastan, M. B. Cell cycle control and cancer. Science 1994, 266, 1821-1828.
4. Hunter, T.; Pines, J. Cyclins and cancer. II: Cyclin D and CDK inhibitors come of age. Cell 1994, 79, 573-582.
5. Sherr, C. J. Cancer cell cycles. Science 1996, 274, 1672-1677.
6. Meijer, L. Chemical inhibitors of cyclin-dependent kinases. In Progress in Cell Cycle Research; Meijer, L., Guidet, S., Tung, H. Y. L., Eds.; Plenum Press: New York, 1995; Vol. 1, pp 351-363.
7. Meijer, L. Chemical inhibitors of cyclin-dependent kinases. Trends Cell Biol. 1996, 6, 393-397.
8. Meijer, L.; Kim, S.-H. Chemical inhibitors of cyclin-dependent kinases. Methods Enzymol 1997, 283, 113-128.
9. Coleman, K. G.; Lyssikatos, J. P.; Ynag, B. V. Chemical inhibitors of cyclin-dependent kinases. Annu. Rep. Med. Chem. 1997, 32, 171-179.
10. Yamamoto, H.; Monden, T.; Miyoshi, H.; Izawa, H.; Ikeda, K.; Tsujie, M.; Ohnishi, T.; Sekimoto, M.; Tomita, N.; Monden, M. Cdk2/cdc2 expression in colon carcinogenesis and effects of cdk2/ cdc2 inhibitor in colon cancer cells. Int. J. Oncol. 1998, 13, 233-239.
11. Wada, M.; Hosotani, R.; Lee, J.-U.; Doi, R.; Koshiba, T.; Fujimoto, K.; Miyamoto, Y.; Tsuji, S.; Nakajima, S.; Okuyama, A.; Imamura, M. An exogenous cdk inhibitor, butyrolactone-I, induces apoptosis with increased Bax/Bcl-2 ratio in p53-mutated pancreatic cancer cells. Anticancer Res. 1998, 18, 2559-2566.
12. Sedlacek, H. H.; Czech, J.; Naik, R.; Kaur, G.; Worland, P.; Losiewicz, M.; Parker, B.; Carlson, B.; Smith, A.; Senderowicz, A.; Sausville, E. Flavopiridol (L86-8275, NSC-649890), a new kinase inhibitor for tumor therapy. Int. J. Oncol. 1996, 9, 1143-1168.
13. Senderowicz, A. M.; Headlee, D.; Stinson, S. F.; Lush, R. M.; Kalil, N.; Villalba, L.; Hill, K.; Steinberg, S. M.; Figg, W. D.; Tompkins, A.; Arbuck, S. G.; Sausville, E. A. Phase I trial of continuous infusion flavopiridol, a novel cyclin-dependent kinase inhibitor, in patients with refractory neoplasms. J. Clin. Oncol. 1998, 16, 2986-2999.
14. Vesely, J.; Havlicek, L.; Strnad, M.; Blow, J. J.; Donella-Deana, A.; Pinna, L.; Letham, D. S.; Kate, J.-Y.; Detivaud, L.; Leclerc, S.; Meijer, L. Inhibition of cyclin-dependent kinases by purine analogues. Eur. J. Biochem. 1994, 224, 771-786.
15. Meijer, L.; Borgne, A.; Mulner, O.; Chong, J. P. J.; Blow, J. J.; Inagaki, N.; Inagaki, M.; Delcros, J.-G.; Moulinoux, J.-P. Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. Eur. J. Biochem. 1997, 243, 527-536.
16. Havlicek, L.; Hanus, J.; Vesely, J.; Leclerc, S.; Meijer, L.; Shaw, G.; Strnad, M. Cytokinin-derived cyclin-dependent kinase inhibitors: Synthesis and cdc2 inhibitory activity of olomoucine and related compounds. J. Med. Chem. 1997, 40, 408-412.
17. Gray, N. S.; Wodicka, L.; Thunnissen, A.-M. W. H.; Norman, T. C.; Kwon, S.; Espinoza, F. H.; Morgan, D. O.; Barnes, G.; Leclerc, S.; Meijer, L.; Kim, S.-H.; Lockhart, D. J.; Schultz, P. G. Exploiting chemical libraries, structure, and genomics in the search of kinase inhibitors. Science 1998, 281, 533-538.
18. De Azevedo, W. F.; Leclerc, S.; Meijer, L.; Havlicek, L.; Strnad, M.; Kim, S.-H. Inhibition of cyclin-dependent kinases by purine analogues. Crystal structure of human cdk2 complexed with roscovitine. Eur. J. Biochem. 1997, 243, 518-526.
19. Schulze-Gahmen, U.; Brandsen, J.; Jones, H. D.; Morgan, D. O.; Meijer, L.; Vesely, J.; Kim, S.-H. Multiple modes of ligand recognition: crystal structures of cyclin-dependent protein kinase 2 in complex with ATP and two inhibitors, olomoucine and isopentenyladenine. Proteins: Struct., Funct., Genet. 1995, 22, 378-391.
20. Kim, S.-H. Structure-based inhibitor design for CDK2, a cell cycle controlling protein kinase. Pure Appl. Chem. 1998, 70, 555-565.
21. Paull, K. D.; Shoemaker, R. H.; Hodes, L.; Monks, A.; Scudiero, D. A.; Rubinstein, L.; Plowman, J.; Boyd, M. R. Display and analysis of patterns of differential activity of drugs against human tumor cell lines: development of meangraph and COMPARE algorithm. J. Natl. Cancer Inst. 1989, 81, 1088-1092.
22. Kunick, C. Synthese von 7,12-Dihydro-indolo[3,2-d][1]benzazepin-6-(5H)-onen und 6, 11-Dihydro-thieno-[3′,2′:2,3]azepino[4,5-b]-indol-5(4H)-on. Arch. Pharm. (Weinheim) 1992, 325, 297-299.
23. Zaharevitz, D. W.; Gussio, R.; Leost, M.; Senderowicz, A.; Lahusen, T.; Kunick, C.; Meijer, L.; Sausville, E. A. Discovery and initial characterization of the paullones, a novel class of small-molecule inhibitors of cyclin-dependent kinases. Cancer Res., in press. A presentation of the molecular modeling results and methods included in this paper is accessible via the Internet from the following web site: Zaharevitz, D. W.; Gussio, R.; Leost, M.; Senderowicz, A.; Lahusen, T.; Kunick, C.; Meijer, L.; Sausville, E. A. Model of kenpaullone (NSC-664704) fit in the ATP site of CDK2. URL: http://dtp.nci.nih.gov/Docs/Branches/Itb/ tsddg/paullones/paullone.html.
24. Zaharevitz, D. W.; Gussio, R.; Leost, M.; Senderowicz, A.; Lahusen, T.; Kunick, C.; Meijer, L.; Sausville, E. A. Discovery and initial characterization of the paullones, a novel class of small-molecule inhibitors of cyclin-dependent kinases. Cancer Res., in press. A presentation of the molecular modeling results and methods included in this paper is accessible via the Internet from the following web site: Zaharevitz, D. W.; Gussio, R.; Leost, M.; Senderowicz, A.; Lahusen, T.; Kunick, C.; Meijer, L.; Sausville, E. A. Model of kenpaullone (NSC-664704) fit in the ATP site of CDK2. URL: http://dtp.nci.nih.gov/Docs/Branches/Itb/ tsddg/paullones/paullone.html.
25. Schulze-Gahmen, U.; De Bondt, H. L.; Kim, S.-H. High-resolution crystal structures of human cyclin-dependent kinase 2 with and without ATP: bound waters and natural ligand as guides for inhibitor design. J. Med. Chem. 1996, 39, 4540-4546.
26. Witte, J.; Boekelheide, V. Stereoselective syntheses of isoquinuclidones. II. J. Org. Chem. 1972, 37, 2849-2853.
27. Rivett, D. E.; Stewart, F. H. C. Formation of substituted 1-benzazepine-2,5-diones. Aust. J. Chem. 1978, 31, 439-443.
28. Rees, A. H. Azatropolones. J. Chem. Soc. 1959, 3111-3116.
29. Moriconi, E. J.; Maniscalco, I. A. π-Equivalent heterocyclic congeners of tropone. Azatropones. J. Org. Chem. 1972, 37, 208-215.
30. Jones, G. Some basic and acidic derivatives of 2,5-dihydro-1H-1-benzazepine as potential therapeutic agents. J. Chem. Soc. 1967, 1808-1813.
31. James, D. M.; Rees, A. H. A chemical and pharmacological study of some compounds derived from 3,4-xylidine. J. Med. Pharm. Chem. 1962, 5, 1234-1239.
32. Chen, W.-Y.; Gilman, N. W. Synthesis of 7-phenylpyrimido[5,4-d][1]benzazepin-2-ones. J. Heterocycl. Chem. 1983, 20, 663-666.
33. Rossi, S.; Micheli, M.; Giannotti, M.; Salvatori, A.; Peruzzi, G. Benzocondensed heptaatomic heterocycles and their derivatives. VII. Synthesis of benzazepines and benzazepinones analogues of known anxiolytic drugs. Gazz. Chim. Ital. 1981, 11, 365-370.
34. Kunick, C. Synthese [b]-kondensierter Azepindione durch De-alkoxycarbonylierung. Arch. Pharm. (Weinheim) 1961, 324, 579-581.
35. Kunick, C.; Link, A.; Hropot, M. Synthesis and in vivo testing of a potential aquaretic agent. Pharmazie 1996, 51, 601-602.
36. Kunick, C. Synthese und konformative Flexibilität von 4,9-Dihydroindolo[3,2-d][1,2,4]triazolo[4,3-a]benzazepinen. Liebigs Ann. Chem. 1993, 1141-1143.
37. Monks, A.; Scudiero, D. A.; Johnson, G. S.; Paull, K. D.; Sausville, E. A. The NCI anti-cancer drug screen: a smart screen to identify effectors of novel targets. Anti-Cancer Drug Des. 1997, 12, 533-541.
38. Robert, J. Anticancer screening with in vitro models. Drugs Future 1997, 22, 739-746.
39. Boyd, M. R.; Paull, K. D.; Rubinstein, L. R. Data display and analysis strategies for the NCI disease-oriented in vitro antitumor drug screen. In Developments in Oncology. Twenty-Second Annual Cancer Symposium 1990, Detroit, Michigan; Valeriote, F. A., Corbett, T. H., Baker, L. H., Eds.; Kluwer Academic Publishers: Boston, 1992; pp 11-34.
40. Bates, S. E.; Fojo, A. T.; Weinstein, J. N.; Myers, T. G.; Alvarez, M.; Paull, K. D.; Chabner, B. A. Molecular targets in the National Cancer Institute drug screen. J. Cancer Res. Clin. Oncol. 1995, 121, 495-500.
41. Weinstein, J. N.; Myers, T. G.; O'Connor, P. M.; Friend, S. H.; Fornace, A. J., Jr.; Kohn, K. W.; Fojo, T.; Bates, S. E.; Rubinstein, L. V.; Anderson, N. L.; Buolamwini, J. K.; van Osdol, W. W.; Monks, A. P.; Scudiero, D. A.; Sausville, E. A.; Zaharevitz, D. W.; Bunow, B.; Viswanadhan, V. N.; Johnson, G. S.; Wittes, R. E.; Paull, K. D. An information-intensive approach to the molecular pharmacology of cancer. Science 1997, 275, 343-349.
42. Boyd, M. R.; Paull, K. D. Some practical considerations and applications of the National Cancer Institute in vitro anticancer drug discovery screen. Drug Dev. Res. 1995, 34, 91-109.
43. Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, J.; Vistica, D.; Warren, J. T.; Bokesch, H.; Kenney, S.; Boyd, M. R. New colorimetric cytotoxicity assay for anticancer drug screen-ing. J. Natl. Cancer Inst. 1990, 82, 1107-1112.
44. Rubinstein, L. V.; Shoemaker, R. H.; Paull, K. D.; Simon, R. M.; Tosini, S.; Skehan, P.; Scudiero, D. A.; Monks, A.; Boyd, M. R. Comparison of in vitro anticancer drug-screening data generated with a tetrazolium assay versus a protein assay against a diverse panel of human tumor cell lines. J. Natl. Cancer Inst. 1990, 82, 1113-1118.
45. Monks, A.; Scudiero, D.; Skehan, P.; Shoemaker, R.; Paull, K.; Vistica, D.; Hose, C.; Langley, J.; Cronise, P.; Vaigro-Wolff, A.; Gray-Goodrich, M.; Campbell, H.; Mayo, J.; Boyd, M. Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. J. Natl. Cancer Inst. 1991, 83, 757-766.
46. Haq, M. A.; Rây, J. N.; Tuffail-Malkana, M. Quinoline Derivatives. Part III. β-2-Amino-4:5-dimethoxy-benzoylpropionic acid and its derivatives. J. Chem. Soc. 1934, 1326-1328.