Synthesis and evaluation of indenopyrazoles as cyclin-dependent kinase inhibitors. 2. Probing the indeno ring substituent pattern

Journal of Medicinal Chemistry

Volumn 45, Issue 24, 2002, Pages 5224-5232

  Nugiel, David A ^a   Vidwans, Anup ^a   Etzkorn, Anna Marie ^a   Rossi, Karen A ^a   Benfield, Pamela A ^a   Burton, Catherine R ^a   Cox, Sarah ^a   Doleniak, Deborah ^a   Seitz, Steven P ^a  

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 (4 METHOXYPHENYL) 2H 2,3 DIAZAPENTALENO[1,2 B]NAPHTHALEN 10 ONE; 1 (4 METHOXYPHENYL) 2H 2,3,4 TRIAZACYCLOPENTA[A]INDEN 8 ONE; 1 (4 METHOXYPHENYL) 2H 2,3,5 TRIAZACYCLOPENTA[A]INDEN 8 ONE; 3 (4 METHOXYPHENYL) 2 METHYL 2H INDENO[1,2 C]PYRAZOL 4 ONE; 3 (4 METHOXYPHENYL) 2 PHENYL 2H INDENO[1,2 C]PYRAZOL 4 ONE; 3 (4 METHOXYPHENYL) 2H INDENO[1,2 C]PYRAZOL 4 ONE; 5 ACETAMIDO 3 (4 METHOXYPHENYL) 2H INDENO[1,2 C]PYRAZOL 4 ONE; 5 HYDROXY 3 (4 METHOXYPHENYL) 2H INDENO[1,2 C]PYRAZOL 4 ONE; 6 AMINO 3 (4 METHOXYPHENYL) 2H INDENO[1,2 C]PYRAZOL 4 ONE; 6 HYDROXY 3 (4 METHOXYPHENYL) 2H INDENO[1,2 C]PYRAZOL ONE; 6,7 DICHLORO 3 (4 METHOXYPHENYL) 2 PHENYL 2H INDENO[1,2 C]PYRAZOL 4 ONE; ADENOSINE TRIPHOSPHATE; CHEMICAL COMPOUND; CYCLIN DEPENDENT KINASE INHIBITOR; FUNCTIONAL GROUP; PHOSPHOTRANSFERASE; PLASMA PROTEIN; PROTEIN SUBUNIT; PYRAZOLE DERIVATIVE; SEMICARBAZIDE DERIVATIVE; SERINE; THREONINE; UNCLASSIFIED DRUG;

ARTICLE; CELL LINE; COLON CANCER; DNA PROBE; ENZYME BINDING; EVALUATION; FIBROBLAST CULTURE; MOLECULAR MODEL; NONHUMAN; PHARMACOPHORE; PROTEIN BINDING; SYNTHESIS;

ANTINEOPLASTIC AGENTS; BLOOD PROTEINS; CDC2-CDC28 KINASES; CELL DIVISION; CELL LINE; CYCLIN-DEPENDENT KINASE 2; CYCLIN-DEPENDENT KINASE 4; CYCLIN-DEPENDENT KINASES; ENZYME INHIBITORS; HUMANS; KINETICS; MODELS, MOLECULAR; MORPHOLINES; PROTEIN BINDING; PROTEIN-SERINE-THREONINE KINASES; PROTO-ONCOGENE PROTEINS; PYRAZOLES; STRUCTURE-ACTIVITY RELATIONSHIP; TUMOR CELLS, CULTURED;

EID: 0037153230     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm020171+     Document Type: Article

References (40)

1. Pardee, A. B. G1 events and regulation of cell proliferation. Science 1989, 246, 603-608.
2. Meijer, L.; Guidet, S.; Philippe, M. Progress in Cell Cycle Research; Plenum: New York, 1997; Vol. 3.
3. (a) Draetta, G.; Pagano, M. Cell cycle control and cancer. Annu. Rep. Med. Chem. 1996, 31, 241-248.
4. (b) Hartwell, L. H.; Kastan, M. B. Cell cycle control and cancer. Science 1994, 266, 1821-1828.
5. (c) Hunter, T.; Pines, J. Cyclins and cancer II: Cyclin D and CDK inhibitors come of age. Cell 1994, 79, 573-582.
6. (a) Toogood, P. L. Cyclin-dependent kinase inhibitors for treating cancer. Med. Res. Rev. 2001, 21 (6), 487-498.
7. (b) Fischer, P. M. Recent advances and new directions in the discovery and development of cyclin-dependent kinase inhibitors. Curr. Opin. Drug Discovery Dev. 2001, 4 (5), 623-634.
8. (c) Meijer, L. Cyclin-dependent kinases inhibitors as potential anticancer, antineuro-degenerative, antiviral and antiparasitic agents. Drug Resist. Updates 2000, 3 (2), 83-88.
9. (d) Sielecki, T. M.; Boylan, J. F.; Benfield, P. A.; Trainor, G. L. Cyclin-dependent kinase inhibitors: Useful targets in cell cycle regulation. J. Med. Chem. 2000, 43 (1), 1.
10. (a) Vesely, J.; Havlicek, L.; Strnad, M.; Blow, J. J.; Donella-Deana, A.; Pinna, L.; Letham, D. S.; Kato, J.-Y.; Detivaud, L.; Leclerc, S.; Meijer, L. Inhibition of cyclin-dependent kinases by purine analogues. Eur. J. Biochem. 1994, 224, 771-786.
11. (b) Gray, N. S.; Wodicka, L.; Thunnissen, A.-M.; 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.
12. (c) Schultz, C.; Link, A.; Leost, M.; Zaharevitz, D. W.; Gussio, R.; Sausville, E. A.; Meijer, L.; Kunick, C. Paullones, a series of cyclin-dependent kinase inhibitors: Synthesis, evaluation of CDK1/cyclin B inhibition, and in vitro antitumor activity. J. Med. Chem. 1999, 42 (23), 2909-2919.
13. (d) Barvian, M.; Boschelli, D. H.; Cossrow, J.; Dobrusin, E.; Fattaey, A.; Fritsch, A.; Fry, D.; Harvey, P.; Keller, P.; Garrett, M.; La, F.; Leopold, W.; McNamara, D.; Quin, M.; Trumpp-Kallmeyer, S.; Toogood, P.; Wu, Z.; Zhang, E. Pyrido[2,3-d]pyrimidin-7-one inhibitors of cyclin-dependent kinases. J. Med. Chem. 2000, 43 (24), 4606-4616.
14. (e) Arris, C. E.; Boyle, F. T.; Calvert, A. H.; Curtin, N. J.; Endicott, J. A.; Garman, E. F.; Gibson, A. E.; Golding, B. T.; Grant, S.; Griffin, R. J.; Jewsbury, P.; Johnson, L. N.; Lawrie, A. M.; Ne, D. R. Identification of novel purine and pyrimidine cyclin-dependent kinase inhibitors with distinct molecular interactions and tumor cell growth inhibition profiles. J. Med. Chem. 2000, 43 (15), 2797-2804.
15. (a) 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.
16. (b) 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.
17. (c) Akinaga, S.; Sugiyama, K.; Akiyama, T. UCN-01 (7-hydroxystaurosporine) and other indolocarbazole compounds: A new generation of anticancer agents for the new century? Anti-Cancer Drug Des. 2000, 15 (1), 43-52.
18. Nugiel, D. A.; Etzkorn, A. M.; Vidwans, A.; Benfield, P. A.; Boisclair, M.; Burton, C. R.; Cox, S.; Czerniak, P. M.; Doleniak, D.; Seitz, S. P Indenopyrazoles as novel cyclin dependent kinase (CDK) inhibitors. J. Med. Chem. 2001, 44, 1334-1336. Part 1 in this series.
19. Yue, E. W.; Higley, C. A.; DiMeo, S. V.; Carini, D. J.; Nugiel, D. A.; Benware, C.; Benfield, P. A.; Burton, C. R.; Cox, S.; Grafstrom, R. H.; Boylan, J. F.; Muckelbauer, J. K.; Smallwood, A. M.; Chen, H.; Chang, C.-H.; Seitz, S. P.; Trainor, G. L. Synthesis and evaluation of indenopyrazoles as cyclin-dependent kinase inhibitors. 3. Structure activity relationships at C3. J. Med. Chem. 2002, 45, 5233-5248.
20. Kilgore, L. B.; Ford, J. H.; Wolfe, W. C. Insecticidal Properties of 1,3-Indandiones Ind. Eng. Chem. 1942, 34 (4), 494-497.
21. Activity against c-Abl was measured for 3b,d and found to be 6.5 and 25 μM, respectively.
22. (a) Dreyer, M. K.; Borcherding, D. R.; Dumont, J. A.; Peet, N. P.; Tsay, J. T.; Wright, P. S.; Bitonti, A. J.; Shen, J.; Kim, S.-H. Crystal structure of human cyclin-dependent kinase 2 in complex with the adenine-derived inhibitor H717. J. Med. Chem. 2001, 44 (4), 524-530.
23. (b) De Bondt, H. L.; Rosenblatt, J.; Jancarik, J.; Jones, H. D.; Morgan, D. O.; Kim, S.-H. Crystal structure of cyclin-dependent kinase 2. Nature 1993, 363, 595-602.
24. (c) Lawrie, A. M.; Noble, M. E. M.; Tunnah, P.; Brown, N. R.; Johnson, L. N.; Endicott, J. A. Protein kinase inhibition by staurosporine revealed in details of the molecular interaction with CDK2. Nat. Struct. Biol. 1997, 4, 796-801.
25. (d) De Azevedo, W. F.; Mueller-Dieckmann, H.-J.; Schulze-Gahmen, U.; Worland, P. J.; Sausville, E.; Kim, S.-H. Structural basis for specificity and potency of a flavonoid inhibitor of human CDK2, a cell cycle kinase. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 2735-2740.
26. (a) Jeffrey, P. D.; Russo, A. A.; Polyak, K.; Gibbs, E.; Hurwitz, J.; Massague, J.; Pavletich, N. P. Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex. Nature 1995, 376, 313-320.
27. (b) Russo, A. A.; Jeffrey, P. D.; Patten, A. K.; Massague, J.; Pavletich, N. P. Crystal structure of the p27 Kip1 cyclin-dependent kinase inhibitor bound to the cyclin A-CDK2 complex. Nature 1996, 382, 325-331.
28. Ducrot, P.; Legraverend, M.; Grierson, D. S. 3D-QSAR CoMFA on cyclin-dependent kinase inhibitors. J. Med. Chem. 2000, 43, 4098-4108.
29. 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.
30. Solubility for indenopyrazole analogues was determined using a buffered 5% mannitol solution with a pH of 3.5; 6a = 0.01 mg/mL; 6c = 0.72 mg/mL; 6j = 0.43 mg/mL; 6p = 0.38 mg/mL; 11a = <0.001 mg/mL.
31. A model of 11i bound in the ATP binding pocket of CDK4 shows the molecule overlapping with 3c in an identical orientation except for the additional atoms that make up the semicarbazide moiety. The proximity of Asp 156 to the acetamide carbon of 3c in Figure 2 indicates how a hydrogen bond could be envisioned by replacing the acetamide carbon atom with a NH group.
32. 50 values greater than 250 μM.
33. Jeffrey, P. D.; Russo, A. A.; Polyak, K.; Gibbs, E.; Hurwitz, J.; Massague, J.; Pavletich, N. P. Mechanism of CDK activation revealed by the structure of a cyclin A CDK2 complex. Nature 1995, 376, 313-320.
34. Sali, A.; Blundell, T. L. Comparative protein modeling by satisfaction of spatial restraints. J. Mol. Biol. 1993, 234 (3), 779-815.
35. Vriend, G. WHAT IF: a molecular modeling and drug design program. J. Mol. Graphics 1990, 8 (1), 52-56.
36. 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.
37. Xu, X.; Nakano, T.; Wick, S.; Dubay, M.; Brizuela, L. Mechanism of CDK2/cyclin E inhibition by p27 and p27 phosphorylation. Biochemistry 1999, 38, 8713-8722.
38. Wick, S. T.; Dubay, M. M.; Imanil, I.; Brizuela, L. Biochemical and mutagenic analysis of the melanomatumor suppressor gene product/p16. Oncogene 1995, 11, 2013-2019.
39. Carlson, B. A.; Dubay, M. M.; Sausville, E. A.; Brizuela, L.; Worland, P. J. Flavopiridol indices G1 arrest with inhibition of cyclin dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells. Cancer Res. 1996, 56, 2973-2978.
40. 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 screening. J. Natl. Cancer Inst. 1990, 82 (13), 1107-1112.