Multisubstituted quinoxalines and pyrido[2,3-d]pyrimidines: Synthesis and SAR study as tyrosine kinase c-Met inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 22, Issue 20, 2012, Pages 6368-6372

  Wu, Kui ^a   Ai, Jing ^b   Liu, Qiufeng ^c   Chen, Tiantian ^c   Zhao, Ailing ^c   Peng, Xia ^b   Wang, Yuanxiang ^c   Ji, Yinchun ^b   Yao, Qizheng ^a   Xu, Yechun ^c   Geng, Meiyu ^b   Zhang, Ao ^c  

^a CHINA PHARMACEUTICAL UNIVERSITY   (China)

^b INSTITUTE OF GEOLOGY AND GEOPHYSICS   (China)

^c SHANGHAI INSTITUTE OF MATERIA MEDICA   (China)

Author keywords

3,5 Diamino 7 trifluoroquinoline; Antitumor activity; C Met kinase; hERG; Structure activity relationship (SAR)

Indexed keywords

ANTINEOPLASTIC AGENT; CRIZOTINIB; PROTEIN TYROSINE KINASE C MET INHIBITOR; PROTEIN TYROSINE KINASE INHIBITOR; PYRIDO[2,3 D]PYRIMIDINE DERIVATIVE; QUINOLINE; QUINOXALINE; QUINOXALINE DERIVATIVE; UNCLASSIFIED DRUG; ZGWATINIB;

ANTINEOPLASTIC ACTIVITY; ARTICLE; CHEMICAL REACTION; CONFORMATIONAL TRANSITION; CRYSTAL STRUCTURE; DRUG DESIGN; DRUG POTENCY; DRUG SYNTHESIS; ENZYME INHIBITION; HUMAN; IC 50; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS; SUBSTITUTION REACTION;

ANTINEOPLASTIC AGENTS; HUMANS; INHIBITORY CONCENTRATION 50; MOLECULAR DOCKING SIMULATION; NEOPLASMS; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS C-MET; PYRIMIDINES; QUINOXALINES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84866737081     PISSN: 0960894X     EISSN: 14643405     Source Type: Journal    
DOI: 10.1016/j.bmcl.2012.08.075     Document Type: Article

References (29)

1. L. Trusolino, and P.M. Comoglio Nat. Rev. Cancer. 2 2002 289
2. C. Birchmeier, W. Birchemier, E. Gherardi, and G.F. Vande Woude Nat. Rev. Mol. Cell Biol. 4 2003 915
3. J.A. Aguirre Ghiso, D.F. Alonso, E.F. Farías, D.E. Gomez, and E.B. de Kier Joffè Eur. J. Biochem. 263 1999 295
4. C. Parr, G. Watkins, R.E. Mansel, and W.G. Jiang Clin. Cancer Res. 10 2004 202
5. S. Rong, S. Segal, M. Anver, J.H. Resau, and G.F. Vande Woude Proc. Natl. Acad. Sci. U.S.A. 91 1994 4731
6. S. Bellusci, G. Moens, G. Gaudino, P. Comoglio, T. Nakamura, J.P. Thiery, and J. Jouanneau Oncogene 9 1994 1091
7. M. Jeffers, S. Rong, M. Anver, and G.F. Vande Woude Oncogene 13 1996 853
8. H. Takayama, W.J. LaRochelle, R. Sharp, T. Otsuka, P. Kriebel, M. Anver, S.A. Aaronson, and G. Merlino Proc. Natl. Acad. Sci. U.S.A. 94 1997 701
9. T. Otsuka, H. Takayama, R. Sharp, G. Celli, W.J. LaRochelle, D.P. Bottaro, N. Ellmore, W. Vieira, J.W. Owens, M. Anver, and G. Merlino Clin. Cancer Res. 58 1998 5157
10. O. Abidoye, N. Murukurthy, and R. Salgia Rev. Recent Clin. Trials. 2 2007 143
11. P.M. Comoglio, S. Giordano, and L. Trusolino Nat. Rev. Drug Disc. 7 2008 504
12. J.P. Eder, G.F. Vande Woude, S.A. Boerner, and P.M. LoRusso Clin. Cancer Res. 15 2009 2207
13. H.Y. Zou, Q. Li, J.H. Lee, M.E. Arango, S.R. McDonnell, S. Yamazaki, T.B. Koudriakova, G. Alton, J.J. Cui, P.P. Kung, M.D. Nambu, G. Los, S.L. Bender, B. Mroczkowski, and J.G. Christensen Clin. Cancer Res. 67 2007 4408
14. X. Wang, P. Le, C. Liang, J. Chan, D. Kiewlich, T. Miller, D. Harris, L. Sun, A. Rice, S. Vasile, R.A. Blake, A.R. Howlett, N. Patel, G. McMahon, and K.E. Lipson Mol. Cancer Ther. 2 2003 1085
15. Fujiwara, Y.; Senga, T.; Nishitoba, T.; Osawa, T.; Miwa, A.; Nakamura, K. PCT Int. Appl. WO2003000660A1, 2003.
16. M. Zillhardt, S.M. Park, I.L. Romero, K. Sawada, A. Montag, T. Krausz, S.D. Yamada, M.E. Peter, and E. Lengyel Clin. Cancer Res. 17 2011 4042
17. G.M. Schroeder, Y. An, Z.H. Cai, X.T. Chen, B.S. Wautlet, D. Wei, D.K. Williams, Y. Zhang, Y. Zhang, J. Fargnoli, and R.M. Borzilleri J. Med. Chem. 52 2009 1251
18. S. Raeppel, S. Claridge, O. Saavedra, F. Gaudette, L. Zhan, M. Mannion, N. Zhou, and A. Vaisburg Bioorg. Med. Chem. Lett. 19 2009 1323
19. J.J. Cui, M. Tran-Dubé, H. Shen, M. Nambu, P.P. Kung, M. Pairish, L. Jia, J. Meng, L. Funk, I. Botrous, M. McTigue, N. Grodsky, K. Ryan, E. Padrique, G. Alton, S. Timofeevski, S. Yamazaki, Q. Li, H. Zou, J. Christensen, B. Mroczkowski, S. Bender, R.S. Kania, and M.P. Edwards J. Med. Chem. 54 2011 6342
20. Y.X. Wang, J. Ai, Y. Wang, Y. Chen, L. Wang, G. Liu, M.Y. Geng, and A. Zhang J. Med. Chem. 54 2011 2127
21. Y.X. Wang, J. Ai, G. Liu, M.Y. Geng, and A. Zhang Org. Biomol. Chem. 9 2011 5930
22. J. Porter, S. Lumb, F. Lecomte, J. Reuberson, A. Maloney, C. Meier, and M. Batchelor Bioorg. Med. Chem. Lett. 19 2009 397
23. El-Haj, M. J.; Dominy, W.B. U.S. Patent 3,962,264, 1976.
24. P. Koning, D. McAndrew, R. Moore, and I. Moses Org. Process Res. Dev. 15 2011 1018
25. Wang, Y.; Ai, J.; Yue, J.; Peng, X.; Ji, Y.; Zhao, A.; Gao, X.; Wang, Y.; Chen, Y.; Liu, G.; Gao, Z.; Geng, M.; Zhang, A. Med. Chem. Commun., accepted for publication. http://dx.doi.org/10.1039/C2MD20192E.
26. +]: 498.1740, found: 498.1743.
27. W. Wang, A. Marimuthu, J. Tsai, A. Kumar, H.I. Krupka, C. Zhang, H. Nguyen, M. Tabrizizad, C. Luu, and B.L. West Proc. Natl. Acad. Sci. U.S.A. 103 2006 3563
28. A.C. Wallace, R.A. Laskowski, and J.M. Thornton Protein Eng. 8 1995 127
29. 27a with certain modifications. The cDNA fragment was cloned into the vector pET28a and the protein was co-expressed with catYopH subcloned in pET15b (164-468AA)2. The expressed c-Met kinase domain was passed through a Ni-NTA column (Qiagen) and further purified by QHP ion exchange column (GE) which eluted with 25 mM Tris pH 8.5, 100 mM NaCl, 10% glycerol, 1 mM DTT. The protein was concentrated to about 10 mg/mL for further crystallization.Cocrystallization of the c-Met kinase domain with compound 2 was carried out by mixing a solution of the protein-ligand complex with an equal volume of precipitant solution (100 mM HEPES pH 7.5, 8% isopropanol, 3 mM TCEP, 16% PEG4K). The protein-ligand complex was prepared by adding the compound to the protein solution to a final concentration of 1 mM of 2. Cocrystallization utilized the vapour-diffusion method in hanging drops. The same cocrystallization protocol was also utilized for compound 15b and the precipitant solution includes 100 mM Tris pH 7.5, 15% glycerol, 12% MPD, 5% isopropanol, 14% PEG5KMME. Crystals were flash frozen in liquid nitrogen in the presence of well solution supplemented with 25% glycerol.