Synthesis, modeling, and RET protein kinase inhibitory activity of 3- and 4-substituted β-carbolin-1-ones

Journal of Medicinal Chemistry

Volumn 51, Issue 24, 2008, Pages 7777-7787

  Cincinelli, Raffaella ^a   Cassinelli, Giuliana ^b   Dallavalle, Sabrina ^a   Lanzi, Cinzia ^b   Merlini, Lucio ^a   Botta, Maurizio ^c   Tuccinardi, Tiziano ^d   Martinelli, Adriano ^d   Penco, Sergio ^a   Zunino, Franco ^b  

^a UNIVERSITY OF MILAN   (Italy)

^b NATIONAL CANCER INSTITUTE   (Italy)

^c UNIVERSITY OF SIENA   (Italy)

^d UNIVERSITY OF PISA   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

3 [(5,6 DIMETHOXY 1 METHYL 1H INDOLE 2 CARBONYL)AMINO]PROPIONIC ACID; 3 [(5,6 DIMETHOXY 1 METHYL 1H INDOLE 2 CARBONYL)AMINO]PROPIONIC ACID ETHYL ESTER; 3 [(5,6 DIMETHOXY 1H INDOLE 2 CARBONYL)AMINO]PROPIONIC ACID; 3 [(5,6 DIMETHOXY 1H INDOLE 2 CARBONYL)AMINO]PROPIONIC ACID ETHYL ESTER; 3,10 DIHYDRO 2H AZEPINO[3,4 B]INDOL 1 ONE DERIVATIVE; 5 (4 HYDROXYPHENYL) 7,8 DIMETHOXY 10 METHYL 3,10 DIHYDRO 2H AZEPINO[3,4 B]INDOL 1 ONE; 5 (4 HYDROXYPHENYL) 7,8 DIMETHOXY 2 (4 METHOXYBENZYL) 10 METHYL 3,10 DIHYDRO 2H AZEPINO[3,4 B]INDOL 1 ONE; 5 (4 HYDROXYPHENYL) 7,8 DIMETHOXY 2,10 DIMETHYL 3,10 DIHYDRO 2H AZEPINO[3,4 B]INDOL 1 ONE; 5 (4 HYDROXYPHENYL) 7,8 DIMETHOXY 3,10 DIHYDRO 2H AZEPINO[3,4 B]INDOL 1 ONE; 5,6 DIMETHOXY 1 METHYL 1H INDOLE 2 CARBOXYLIC ACID; 5,6 DIMETHOXY 1 METHYL 1H INDOLE 2 CARBOXYLIC ACID(3 FORMYLPROPYL)AMIDE; 5,6 DIMETHOXY 1 METHYL 1H INDOLE 2 CARBOXYLIC ACID(3 HYDROXYBUTYL)AMIDE; 5,6 DIMETHOXY 1 METHYL 1H INDOLE 2 CARBOXYLIC ACID(3 HYDROXYPROPYL)AMIDE; 5,6 DIMETHOXY 1 METHYL 1H INDOLE 2 CARBOXYLIC ACID(3 OXOBUTYL)AMIDE; 7,8 DIMETHOXY 10 (4 METHOXYBENZYL) 3,4 DIHYDRO 2H,10H AZEPINO[3,4 B]INDOLE 1,5 DIONE; 7,8 DIMETHOXY 10 METHYL 3,10 DIHYDRO 2H AZEPINO[3,4 B]INDOL 1 ONE; 7,8 DIMETHOXY 10 METHYL 3,4 DIHYDRO 2H,10H AZEPINO[3,4 B]INDOLE 1,5 DIONE; 7,8 DIMETHOXY 2 (4 METHOXYBENZYL) 10 METHYL 3,4 DIHYDRO 2H,10H AZEPINO[3,4 B]INDOLE 1,5 DIONE; 7,8 DIMETHOXY 2,10 DIMETHYL 3,4 DIHYDRO 2H,10H AZEPINO[3,4 B]INDOLE 1,5 DIONE; 7,8 DIMETHOXY 3,4 DIHYDRO 2H,10H AZEPINO[3,4 B]INDOLE 1,5 DIONE; 7,8 DIMETHOXY 5 (4 METHOXYPHENYL) 10 METHYL 3,10 DIHYDRO 2H AZEPINO[3,4 B]INDOL 1 ONE; 7,8 DIMETHOXY 5,10 DIMETHYL 3,10 DIHYDRO 2H AZEPINO[3,4 B]INDOL 1 ONE; BETA CARBOLIN 1 ONE DERIVATIVE; BETA CARBOLIN 2 ONE DERIVATIVE; PROTEIN KINASE INHIBITOR; PROTEIN RET; TRIFLUOROMETHANESULFONIC ACID 7,8 DIMETHOXY 1 OXO 1,2,3,10 TETRAHYDROAZEPINO[3,4 B]INDOL 5 YL ESTER; TRIFLUOROMETHANESULFONIC ACID 7,8 DIMETHOXY 2 (4 METHOXYBENZYL) 10 METHYL 1 OXO 1,2,3,10 TETRAHYDROAZEPINO[3,4 B]INDOL 5 YL ESTER; TRIFLUOROMETHANESULFONIC ACID 7,8 DIMETHOXY 2,10 DIMETHYL 1 OXO 1,2,3,10 TETRAHYDROAZEPINO[3,4 B]INDOL 5 YL ESTER; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ANIMAL CELL; ARTICLE; BINDING ASSAY; CELL STRAIN 3T3; CONFORMATIONAL TRANSITION; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG DESIGN; DRUG PROTEIN BINDING; DRUG SCREENING; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME ASSAY; ENZYME INHIBITION; IC 50; MITOSIS INHIBITION; MOLECULAR INTERACTION; MOLECULAR MODEL; NONHUMAN; PROTEIN DOMAIN; STRUCTURE ANALYSIS;

ANIMALS; CARBOLINES; CHEMISTRY, PHARMACEUTICAL; DRUG DESIGN; ENZYME INHIBITORS; HUMANS; HYDROGEN BONDING; INHIBITORY CONCENTRATION 50; MICE; MODELS, CHEMICAL; MODELS, MOLECULAR; MOLECULAR CONFORMATION; NIH 3T3 CELLS; PROTO-ONCOGENE PROTEINS C-RET; THERMODYNAMICS;

EID: 58149086851     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm8007823     Document Type: Article

References (37)

1. Arighi, E.; Borrello, M. G.; Sariola, H. RET tyrosine kinase signaling in development and cancer. Cytokine Growth Factor Rev. 2005, 16, 441-467.
2. Asai, N.; Jijiwa, M.; Enomoto, A.; Hawai, K.; Maeda, K.; Ichiahara, M.; Murakumo, Y.; Takahashi, M. RET receptor signaling: dysfunction in thyroid cancer and Hirschsprung's disease. Pathol. Int. 2006, 56, 164-172.
3. Murakumo, Y.; Jijiwa, M.; Asai, N.; Ichihara, M.; Takahashi, M. RET and neuroendocrine tumors. Pituitary 2006, 9, 179-192.
4. Rosa, D. D.; Ismael, G.; Dal Lago, L.; Awada, A. Molecular-targeted therapies: lessons from years of clinical development. Cancer Treat. Rev. 2008, 34, 61-80.
5. Drosten, M.; Pützer, B. M. Mechanisms of disease: cancer targeting and the impact of oncogenic RET for medullary thyroid carcinoma therapy. Nat. Clin. Pract. 2006, 3, 564-574.
6. De Groot, J. W. B.; Links, T. P.; Plukker, J. T. M.; Lips, C. J. M.; Hofstra, R. M. W. RET as a diagnostic and therapeutic target in sporadic and hereditary endocrine tumors. Endocr. Rev. 2006, 27, 535-560.
7. Cuccuru, G.; Lanzi, C.; Cassinelli, G.; Pratesi, G.; Tortoreto, M.; Petrangolini, G.; Seregni, E.; Martinetti, A.; Laccabue, D.; Zanchi, C.; Zunino, F. Cellular effects and antitumor activity of RET inhibitor RPI-1 on MEN2A-associated medullary thyroid carcinoma. J. Natl. Cancer Inst. 2004, 96, 1006-1014.
8. Drosten, M.; Hilken, G.; Böckmann, M.; Rödicker, F.; Mise, N.; Cranston, A. N.; Dahmen, U.; Ponder, B. A. J.; Pützer, B. M. Role of MEN2A-derived RET in maintenance and proliferation of medullary thyroid carcinoma. J. Natl. Cancer Inst. 2004, 96, 1231-1239.
9. Petrangolini, G.; Cuccuru, G.; Lanzi, C.; Tortoreto, M.; Belluco, S.; Pratesi, G.; Cassinelli, G.; Zunino, F. Apoptotic cell death induction and angiogenesis inhibition in large established medullary thyroid carcinoma xenografts by Ret inhibitor RPI-1. Biochem. Pharmacol. 2006, 72, 405-414.
10. Sharma, S. V.; Settleman, J. Oncogene addiction: setting the stage for molecularly targeted cancer therapy. Genes Dev. 2007, 21, 3214-3231.
11. Cassinelli, G.; Lanzi, C.; Pensa, T.; Gambetta, R. A.; Nasini, G.; Cuccuru, G.; Cassinis, M.; Pratesi, G.; Polizzi, D.; Tortoreto, M.; Zunino, F. Clavilactones, a novel class of tyrosine kinase inhibitors of fungal origin. Biochem. Pharmacol. 2000, 59, 1539-1547.
12. Kundra, P.; Burman, K. D. Thyroid cancer molecular signaling pathways and use of targeted therapy. Endocrinol. Metab. Clin. N. Am. 2007, 36, 839-853.
13. Deshpande, H. A.; Gettinger, S. N.; Sosa, J. A. Novel chemotherapy options for advanced thyroid tumors: small molecules offer great hope. Curr. Opin. Oncol. 2008, 20, 19-24.
14. Schlumberger, M.; Carlomagno, F.; Baudin, E.; Bidart, J. M.; Santoro, M. New therapeutic approaches to treat medullary thyroid carcinoma. Nat. Clin. Pract. 2008, 4, 22-32.
15. Sun, L.; Tran, N.; Tang, F.; App, H.; Hirth, P.; McMahon, G.; Tang, C. Synthesis and biological evaluations of 3-substituted indolin-2-ones: a novel class of tyrosine kinase inhibitors that exhibit selectivity toward particular receptor tyrosine kinases. J. Med. Chem. 1998, 41, 2588-2603.
16. Lanzi, C.; Cassinelli, G.; Cuccuru, G.; Zaffaroni, N.; Supino, R.; Vignati, S.; Zanchi, C.; Yamamoto, M.; Zunino, F. Inactivation of Ret/Ptc1 oncoprotein and inhibition of papillary thyroid carcinoma cell proliferation by indolinone RPI-1. Cell. Mol. Life Sci. 2003, 60, 1449-1459.
17. Lanzi, C.; Cassinelli, G.; Pensa, T.; Cassinis, M.; Gambetta, R. A.; Borrello, M. G.; Menta, E.; Pierotti, M. A.; Zunino, F. Inhibition of transforming activity of the ret/ptc1 oncoprotein by a 2-indolinone derivative. Int. J. Cancer 2000, 85, 384-390.
18. Cassinelli, C.; Lanzi, C.; Petrangolini, G.; Tortoreto, M.; Pratesi, G.; Cuccuru, G.; Laccabue, D.; Supino, R.; Belluco, S.; Favini, E.; Poletti, A.; Zunino, F. Inhibition of c-Met and prevention of spontaneous metastatic spreading by the 2-indolinine RPI-1. Mol. Cancer Ther. 2006, 5, 2388-2397.
19. Sun, L.; Tran, N.; Tang, F.; App, H.; Hirth, P.; McMahon, G.; Tang, C. Synthesis and biological evaluations of 3-substituted indolin-2-ones: a novel class of tyrosine kinase inhibitors that exhibit selectivity toward particular receptor tyrosine kinases. J. Med. Chem. 1998, 41, 2588-2603.
20. Tuccinardi, T.; Manetti, F.; Schenone, S.; Martinelli, A.; Botta, M. Construction and validation of a RET TK catalytic domain by homology modeling. J. Chem. Inf. Model. 2007, 47, 644-655.
21. Mohammadi, M.; McMahon, G.; Sun, L.; Tang, C.; Hirth, P.; Yeh, B. K.; Hubbard, S. R.; Schlessinger, J. Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors. Science 1997, 276, 955-960.
22. Wang, S.; Dong, Y.; Wang, X.; Hu, X.; Liu, J. O.; Hu, Y. 3-Aryl beta-carbolin-1-ones as a new class of potent inhibitors of tumor cell proliferation: synthesis and biological evaluation. Org. Biomol. Chem. 2005, 3, 911-916.
23. Chacun-Lefèvre, B.; Joseph, B.; Mérour, J.-Y. Synthesis and reactivity of azepino[3,4-b]indol-5-yl trifluoromethanesulfonate. Tetrahedron 2000, 56, 4491-4499.
24. Cincinelli, R.; Dallavalle, S.; Merlini, L. Intramolecular Friedel-Crafts reaction of indoles with carbonyl groups: a simple synthesis of 3- and 4-substituted β-carbolin-1-ones. Synlett 2008, 1309-1312.
25. Rizzi, E.; Cassinelli, G.; Dallavalle, S.; Lanzi, C.; Cincinelli, R.; Nannei, R.; Cuccuru, G.; Zunino, F. Synthesis and RET protein kinase inhibitory activity of 3-arylureidobenzylidene-indolin-2-ones. Bioorg. Med. Chem. Lett. 2007, 17, 3962-3968.
26. Knowles, P. P.; Murray-Rust, J.; Kjaer, S.; Scott, R. P.; Hanrahan, S.; Santoro, M.; Ibáñez, C. F.; McDonald, N. Q. Structure and chemical inhibition of the RET tyrosine kinase domain. J. Biol. Chem. 2006, 281, 33577-33587.
27. Jones, G.; Willett, P.; Glen, R. C.; Leach, A. R.; Taylor, R. Development and validation of a genetic algorithm for flexible docking. J. Mol. Biol. 1997, 267, 727-748.
28. Toledo, L. M.; Lydon, N. B.; Elbaum, D. The structure-based design of ATP-site directed protein kinase inhibitors. Curr. Med. Chem. 1999, 6, 775.
29. Traxler, P.; Green, J.; Mett, H.; Sequin, U.; Furet, P. Use of a pharmacophore model for the design of EGFR tyrosine kinase inhibitors: isoflavones and 3-phenyl-4(1H)-quinolones. J. Med. Chem. 1999, 42, 1018-1026.
30. Massova, I.; Kollman, P. A. Combined molecular mechanical and continuum solvent approach (MM-PBSA/GBSA) to predict ligand binding. Perspect. Drug Discovery Des. 2000, 18, 113-135.
31. Rizzo, R. C.; Toba, S.; Kuntz, I. D. A molecular basis for the selectivity of thiadiazole urea inhibitors with stromelysin-1 and gelatinase-A from generalized Born molecular dynamics simulations. J. Med. Chem. 2004, 47, 3065-3074.
32. http://www.pdb.org/.
33. Case, D. A.; Darden, T. A., Cheatham, T. E., III; Simmerling, C. L.; Wang, J.; Duke, R. E.; Luo, R.; Merz, K. M.; Pearlman, D. A.; Crowley, M.; Walker, R. C.; Zhang, W.; Wang, B.; Hayik, S.; Roitberg, A.; Seabra, G.; Wong, K. F.; Paesani, F.; Wu, X.; Brozell, S.; Tsui, V.; Gohlke, H.; Yang, L.; Tan, C.; Mongan, J.; Hornak, V.; Cui, G.; Beroza, P.; Mathews, D. H.; Schafmeister, C.; Ross, W. S.; Kollman, P. A. AMBER 9; University of California: San Francisco, CA, 2006.
34. Maestro, version 7.5; Schrödinger, Inc.: Portland, OR, 1999.
35. Macromodel, version 8.5; Schrödinger, Inc.: Portland, OR, 1999.
36. Essman, U.; Perela, L.; Berkowitz, M. L.; Darden, T.; Lee, H.; Pedersen, L. G. A smooth particle mesh Ewald method. J. Chem. Phys. 1995, 103, 8577-8592.
37. Weiser, J.; Shenkin, P. S.; Still, W. C. Approximate atomic surfaces from linear combinations of pairwise overlaps (LCPO). J. Comput. Chem. 1999, 20, 217-230.