Cdc7 kinase inhibitors: 5-heteroaryl-3-carboxamido-2-aryl pyrroles as potential antitumor agents. 1. Lead finding

Journal of Medicinal Chemistry

Volumn 53, Issue 20, 2010, Pages 7296-7315

  Menichincheri, Maria ^a   Albanese, Clara ^a   Alli, Cristina ^a   Ballinari, Dario ^a   Bargiotti, Alberto ^a   Caldarelli, Marina ^a   Ciavolella, Antonella ^a   Cirla, Alessandra ^a   Colombo, Maristella ^a   Colotta, Francesco ^a   Croci, Valter ^a   Dalessio, Roberto ^a   Danello, Matteo ^a   Ermoli, Antonella ^a   Fiorentini, Francesco ^b   Forte, Barbara ^a   Galvani, Arturo ^a   Giordano, Patrizia ^a   Isacchi, Antonella ^a   Martina, Katia ^a,c   Molinari, Antonio ^b   Moll, Jürgen K ^a   Montagnoli, Alessia ^a   Orsini, Paolo ^a   Orzi, Fabrizio ^a   Pesenti, Enrico ^a   Pillan, Antonio ^a   Roletto, Fulvia ^a   Scolaro, Alessandra ^a   Tatò, Marco ^a   Tibolla, Marcellino ^a   Valsasina, Barbara ^a   Varasi, Mario ^a,d   Vianello, Paola ^a,d   Volpi, Daniele ^a   Santocanale, Corrado ^a,e   Vanotti, Ermes ^a   more..

^a NERVIANO MEDICAL SCIENCES   (Italy)

^b Accelera Srl   (Italy)

^c UNIVERSITY OF TURIN   (Italy)

^d EUROPEAN INSTITUTE OF ONCOLOGY   (Italy)

^e NATIONAL UNIVERSITY OF IRELAND   (Ireland)

Author keywords

[No Author keywords available]

Indexed keywords

2 (2 FLUOROPHENYL) 5 PYRIDIN 4 YL 1H PYRROLE 3 CARBOXAMIDE HYDROCHLORIDE; 2 (3 BROMOPHENYL) 5 PYRIDIN 4 YL 1H PYRROLE 3 CARBOXAMIDE; 2 (3 FLUOROPHENYL) 5 PYRIDIN 4 YL 1H PYRROLE 3 CARBOXAMIDE; 2 (4 BROMOPHENYL) 5 PYRIDIN 4 YL 1H PYRROLE 3 CARBOXYLIC ACID AMIDE; 2 (4 FLUOROPHENYL) 5 PYRIDIN 4 YL 1H PYRROLE 3 CARBOXAMIDE; 2 PHENYL 5 (2 PHENYLAMINOPYRIMIDIN 4 YL) 1H PYRROLE 3 CARBOXAMIDE; 2 PHENYL 5 PYRIDIN 4 YL 1H PYRROLE 3 CARBOXAMIDE; 5 (2 AMINO 5 FLUOROPYRIMIDIN 4 YL) 2 PHENYL 1H PYRROLE 3 CARBOXAMIDE; 5 (2 AMINOPYRIDIN 4 YL) 2 PHENYL 1H PYRROLE 3 CARBOXAMIDE; 5 (2 AMINOPYRIMIDIN 4 YL) 1 (2 HYDROXYETHYL) 2 PHENYL 1H PYRROLE CARBOXAMIDE; 5 (2 AMINOPYRIMIDIN 4 YL) 1 ETHYL 2 PHENYL 1H PYRROLE 3 CARBOXAMIDE; 5 (2 AMINOPYRIMIDIN 4 YL) 1 METHYL 2 PHENYL 1H PYRROLE 3 CARBOXAMIDE; 5 (2 AMINOPYRIMIDIN 4 YL) 2 BENZO[B]THIOPHEN 5 YL 1H PYRROLE 3 CARBOXAMIDE; 5 (2 AMINOPYRIMIDIN 4 YL) 2 NAPHTHALEN 1 YL 1H PYRROLE 3 CARBOXAMIDE; 5 (2 AMINOPYRIMIDIN 4 YL) 2 NAPHTHALEN 2 YL 1H PYRROLE 3 CARBOXAMIDE; 5 (2 AMINOPYRIMIDIN 4 YL) 2 PHENYL 1H PYRROLE 3 CARBOXAMIDE; 5 (2 AMINOPYRIMIDIN 4 YL) 2 PHENYL 1H PYRROLE 3 CARBOXYLIC ACID BENZYLAMIDE; 5 (2 AMINOPYRIMIDIN 4 YL) 2 PHENYL 1H PYRROLE 3 CARBOXYLIC ACID ISOPROPYLAMIDE; 5 (2 AMINOPYRIMIDIN 4 YL) 2 PYRIDIN 2 YL 1H PYRROLE 3 CARBOXAMIDE; 5 (2 AMINOPYRIMIDIN 4 YL) 2 THIOPHEN 2 YL 1H PYRROLE 3 CARBOXAMIDE; 5 (2 AMINOPYRIMIDIN 4 YL) 2 THIOPHEN 3 YL 1H PYRROLE 3 CARBOXAMIDE; 5 (2 AMINOPYRIMIDIN 4 YL) 4 IODO 2 PHENYL 1H PYRROLE 3 CARBOXAMIDE; 5 (3 FLUOROPYRIDIN 4 YL) 2 PHENYL 1H PYRROLE 3 CARBOXAMIDE; 5 PYRIDIN 4 YL 2,3 TOLYL 1H PYRROLE 3 CARBOXAMIDE; 5 PYRIDIN 4 YL 2,4 TOLYL 1H PYRROLE 3 CARBOXAMIDE; 5- (2 AMINOPYRIMIDIN 4 YL) 2 PHENYL 1H PYRROLE 3 CARBOXYLIC ACID; ANTINEOPLASTIC AGENT; CELL DIVISION CYCLE 7 KINASE INHIBITOR; PHOSPHOTRANSFERASE INHIBITOR; UNCLASSIFIED DRUG; UNINDEXED DRUG; 5-(2-AMINO-PYRIMIDIN-4-YL)-2-PHENYL-1H-PYRROLE-3-CARBOXAMIDE; CDC7 PROTEIN, HUMAN; CDC7 PROTEIN, MOUSE; CELL CYCLE PROTEIN; PROTEIN SERINE THREONINE KINASE; PYRIMIDINE DERIVATIVE; PYRROLE DERIVATIVE;

ANIMAL CELL; ANTINEOPLASTIC ACTIVITY; ARTICLE; CELL PROLIFERATION; COLORECTAL CANCER; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG MECHANISM; DRUG POTENCY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME BINDING; HUMAN; HUMAN CELL; IN VITRO STUDY; MOUSE; NEOPLASM; NONHUMAN; OVARY CANCER; RAT; ANIMAL; ANTAGONISTS AND INHIBITORS; BIOAVAILABILITY; CANCER TRANSPLANTATION; CHEMISTRY; DRUG SCREENING; NUDE MOUSE; STRUCTURE ACTIVITY RELATION; SYNTHESIS; TUMOR CELL LINE; XENOGRAFT;

ANIMALS; ANTINEOPLASTIC AGENTS; BIOLOGICAL AVAILABILITY; CELL CYCLE PROTEINS; CELL LINE, TUMOR; DRUG SCREENING ASSAYS, ANTITUMOR; HUMANS; MICE; MICE, NUDE; NEOPLASM TRANSPLANTATION; PROTEIN-SERINE-THREONINE KINASES; PYRIMIDINES; PYRROLES; STRUCTURE-ACTIVITY RELATIONSHIP; TRANSPLANTATION, HETEROLOGOUS;

EID: 77958498566     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm100504d     Document Type: Article

References (30)

1. Chabner, B. A.; Ryan, D. P.; Paz-Arez, L.; Garcia-Carbonero, R.; Calabresi, P. The Pharmacological Basis of Therapeutics; McGraw-Hill: New York, 2001; Chapter 52, pp 1389 - 1460.
2. Longley, D. B.; Johnston, P. G. Molecular mechanisms of drug resistance J. Pathol. 2005, 205, 275-292
3. Bell, S. P.; Dutta, A. DNA replication in eukaryotic cells Annu. Rev. Biochem. 2002, 71, 333-374
4. Jiang, W.; McDonald, D.; Hope, T. J.; Hunter, T. Mammalian Cdc7-Dbf4 protein kinase complex is essential for initiation of DNA replication EMBO J. 1999, 18, 5703-5713
5. Montagnoli, A.; Valsasina, B.; Brotherton, D.; Troiani, S.; Rainoldi, S.; Tenca, P.; Molinari, A.; Santocanale, C. Identification of Mcm2 phosphorylation sites by S-phase-regulating kinases J. Biol. Chem. 2006, 281, 10281-10290
6. Tsuji, T.; Ficarro, S. B.; Jiang, W. Essential role of phosphorylation of MCM2 by Cdc7/Dbf4 in the initiation of DNA replication in mammalian cells Mol. Biol. Cell 2006, 17, 4459-4472
7. Montagnoli, A.; Tenca, P.; Sola, F.; Carpani, D.; Brotherton, D.; Albanese, C.; Santocanale, C. Cdc7 inhibition reveals a p53-dependent replication checkpoint that is defective in cancer cells Cancer Res. 2004, 64, 7110-7116
8. Montagnoli, A.; Valsasina, B.; Croci, V.; Menichincheri, M.; Rainoldi, S.; Marchesi, V.; Tibolla, M.; Tenca, P.; Brotherton, D.; Albanese, C.; Patton, V.; Alzani, R.; Ciavolella, A.; Sola, F.; Molinari, A.; Volpi, D.; Avanzi, N.; Fiorentini, F.; Cattoni, M.; Healy, S.; Ballinari, D.; Pesenti, E.; Isacchi, A.; Moll, J.; Bensimon, A.; Vanotti, E.; Santocanale, C. A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity Nature Chem. Biol. 2008, 4, 357-365
9. Bonte, D.; Lindvall, C.; Liu, H.; Dykema, K.; Furge, K.; Weinreich, M. Cdc7-Dbf4 kinase is overexpressed in multiple cancers and tumor cell lines and is correlated with p53 inactivation Neoplasia 2008, 10, 920-931
10. Kulkarni, A. A.; Kingsbury, S. R.; Tudzarova, S.; Hong, H.-K.; Loddo, M.; Rashid, M.; Rodriguez-Acebes, S.; Prevost, A. T.; Ledermann, J. A.; Stoeber, K.; Williams, G. H. Cdc7 kinase is a predictor of survival and a novel therapeutic target in epithelial ovarian carcinoma Clin. Cancer Res. 2009, 15, 2417-2425
11. Swords, R.; Mahalingam, D.; ODwyer, M.; Santocanale, C.; Kelly, K.; Carew, J.; Giles, F. Cdc7 kinase - a new target for drug development Eur. J. Cancer 2010, 46, 33-40
12. Vanotti, E.; Amici, R.; Bargiotti, A.; Berthelsen, J.; Bosotti, R.; Ciavolella, A.; Cirla, A.; Cristiani, C.; DAlessio, R.; Forte, B.; Isacchi, A.; Martina, K.; Menichincheri, M.; Molinari, A.; Montagnoli, A.; Orsini, P.; Pillan, A.; Roletto, F.; Scolaro, A.; Tibolla, M.; Valsasina, B.; Varasi, M.; Volpi, D.; Santocanale, C. Cdc7 kinase inhibitors: pyrrolopyridinones as potential antitumor agents. 1. Synthesis and structure-activity relationships J. Med. Chem. 2008, 51, 487-501
13. Menichincheri, M.; Bargiotti, A.; Berthelsen, J.; Bertrand, J.; Bossi, R.; Ciavolella, A.; Cirla, A.; Cristiani, C.; Croci, V.; DAlessio, R.; Fasolini, M.; Fiorentini, F.; Forte, B.; Isacchi, A.; Martina, K.; Molinari, A.; Montagnoli, A.; Orsini, P.; Orzi, F.; Pesenti, E.; Pezzetta, D.; Pillan, A.; Poggesi, I.; Roletto, F.; Scolaro, A.; Tatò, M.; Tibolla, M.; Valsasina, B.; Varasi, M.; Volpi, D.; Santocanale, C.; Vanotti, E. First Cdc7 kinase inhibitors: pyrrolopyridinones as potent and orally active antitumor agents. 2. Lead discovery J. Med. Chem. 2009, 52, 293-307
14. Ermoli, A.; Bargiotti, A.; Brasca, M. G.; Ciavolella, A.; Colombo, N.; Fachin, G.; Isacchi, A.; Menichincheri, M.; Molinari, A.; Montagnoli, A.; Pillan, A.; Rainoldi, S.; Riccardi Sirtori, F.; Sola, F.; Thieffine, S.; Tibolla, M.; Valsasina, B.; Volpi, D.; Santocanale, C.; Vanotti, E. Cell Division Cycle 7 Kinase Inhibitors: 1 H -Pyrrolo[2,3- b ]pyridines, Synthesis and Structure-Activity Relationships J. Med. Chem. 2009, 52, 4380-4390
15. Sawa, M.; Masai, H. Drug design with Cdc7 kinase: a potential novel cancer therapy target Drug Des. Dev. Ther. 2009, 2, 255-264
16. Schmuck, C.; Rupprecht, D. The synthesis of highly functionalized pyrroles: a challenge in regioselectivity and chemical reactivity Synthesis 2007, 20, 3095-3110
17. Liu, M.; Wang, S.; Clampit, J. E.; Gum, R. J.; Haasch, D. L.; Rondinone, C. M.; Trevillyan, J. M.; Abad-Zapatero, C.; Fry, E. H.; Sham, H. L.; Liu, G. Discovery of a new class of 4-anilinopyrimidines as potent c-Jun N-terminal kinase inhibitors: synthesis and SAR studies Bioorg. Med. Chem. Lett. 2007, 17, 668-672
18. Wannberg, J.; Dallinger, D.; Kappe, C. O.; Larhed, M. Microwave-Enhanced and Metal-Catalyzed Functionalizations of the 4-Aryl-Dihydropyrimidone Template J. Comb. Chem. 2005, 7, 574-583
19. 2Et à partir du malonate acide déthyle Bull. Soc. Chim. Fr. 1964, 945-951
20. Brooks, D. W.; Lu, L. D.-L.; Masamune, S. C-Acylation under Virtually Neutral Conditions Angew. Chem., Int. Ed. 1979, 18, 72-74
21. Foley, L. H. An efficient synthesis of 2-chloro-3-carboethoxy- or 2-chloro-3-cyano-4,5-disubstituted and 5-substituted pyrroles Tetrahedron Lett. 1994, 35, 5989-5992
22. Bernatowicz, M. S.; Daniels, S. B.; Köster, H. A Comparison of Acid Labile Linkage Agents for the Synthesis of Peptide C-terminal Amides Tetrahedron Lett. 1989, 30, 4645-4648
23. Lipinski, C. A.; Craig, R. H.; Wright, R. B. 2-Amino- and 2-guanidino-4-thiazolylpyrimidines J. Heterocycl. Chem. 1985, 22, 1723-1726
24. Li, J. J.; Corey, E. J. Name Reactions in Heterocyclic Chemistry; John Wiley and Sons: New York, 2004; p 209.
25. Vanotti, E.; Caldarelli, M.; Disingrini, T.; Nesi, M.; Tatò, M.; Vianello, P.; Menichincheri, M. Regioselective halogenation of aminopyrimidinyl-pyrrole carboxylic acid derivatives Tetrahedron 2009, 65, 10418-10423
26. Wang, J.; Scott, A. I. An efficient synthesis of 3-vinylpyrroles by Stille coupling reaction of 3-iodopyrroles with vinyltributyltin Tetrahedron Lett. 1995, 36, 7043-7046
27. Meyer, E. A.; Castellano, R. K.; Diederich, F. Interactions with aromatic rings in chemical and biological recognition Angew. Chem., Int. Ed. 2003, 42, 1210-1250
28. Colombo, M.; Riccardi-Sirtori, F.; Rizzo, V. A fully automated method for accurate mass determination using high-performance liquid chromatography with a quadrupole/orthogonal acceleration time-of-flight mass spectrometer Rapid Commun. Mass Spectrom. 2004, 18, 511-517
29. Pevarello, P.; Brasca, M. G.; Amici, R.; Orsini, P.; Traquandi, G.; Corti, L.; Piutti, C.; Sansonna, P.; Villa, M.; Pierce, B. S.; Pulici, M.; Giordano, P.; Martina, K.; Fritzen, E. L.; Nugent, R. A.; Casale, E.; Cameron, A.; Ciomei, M.; Roletto, F.; Isacchi, A.; Fogliatto, G.; Pesenti, E.; Pastori, W.; Marsiglio, A.; Leach, K. L.; Clare, P. M.; Fiorentini, F.; Varasi, M.; Vulpetti, A.; Warpehoski, M. A. 3-Aminopyrazole inhibitors of CDK2/Cyclin A as antitumor agents. 1. Lead finding J. Med. Chem. 2004, 47, 3367-3380
30. Kerns, E. H.; Di, L.; Petusky, S.; Farris, M.; Ley, R.; Jupp, P. Combined application of parallel artificial membrane permeability assay and Caco-2 permeability assays in drug discovery J. Pharm. Sci. 2004, 93, 1440-1453