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Design and Synthesis of an Anticancer Diarylurea Derivative with Multiple-Kinase Inhibitory Effect

  • Received : 2012.01.05
  • Accepted : 2012.02.06
  • Published : 2012.05.20

Abstract

A diarylurea compound 1 possessing pyrrolo[3,2-$c$]pyridine nucleus was designed and synthesized with structure similarity to Sorafenib. Compound 1 was tested over 60-cancer cell line panel at a single dose concentration of 10 ${\mu}M$ and showed high activity. It was further tested in a five-dose mode to determine its $IC_{50}$, TGI, and $LC_{50}$ values over the 60 cell lines. Compound 1 showed high potency and good efficacy, and was accordingly tested at a single dose concentration of 10 ${\mu}M$ over a panel of 40 kinases. At this concentration, it completely inhibited the enzymatic activities of a number of oncogenic kinases, including ABL, ALK, c-RAF, FLT3, KDR, and TrkB. The target compound was subsequently tested over these 6 kinases in 10-dose testing mode in order to determine its $IC_{50}$ values.

Keywords

References

  1. http://www.who.int/mediacentre/factsheets/fs297/en/
  2. Kolibaba, K. S.; Druker, B. J. Biochim. Biophys. Acta 1997, 1333, 217.
  3. Manning, G.; Whyte, D. B.; Martinez, R.; Hunter, T.; Sudarsanam, S. Science 2002, 298, 1912. https://doi.org/10.1126/science.1075762
  4. Kamb, A.; Wee, S.; Lengauer, C. Nat. Rev. Drug. Discov. 2007, 6, 115. https://doi.org/10.1038/nrd2155
  5. Force, T.; Krause, D. S.; Van Etten, R. A. Nat. Rev. Cancer 2007, 7, 332. https://doi.org/10.1038/nrc2106
  6. Daub, H.; Specht, K.; Ullrich, A. Nat. Rev. Drug Discov. 2004, 3, 1001. https://doi.org/10.1038/nrd1579
  7. Wilhelm, S.; Carter, C.; Lynch, M.; Lowinger, T.; Dumas, J.; Smith, R. A.; Schwartz, B.; Simantov, R.; Kelley, S. Nat. Rev. Drug Discov. 2006, 5, 835. https://doi.org/10.1038/nrd2130
  8. http://www.pslgroup.com/news/content.nsf/medicalnews/852571020057CCF685257384005A45B1?OpenDocument&id=&count=10
  9. El-Gamal, M. I.; Jung, M.-H.; Lee, W. S.; Sim, T.; Yoo, K. H.; Oh, C.-H. Eur. J. Med. Chem. 2011, 46, 3218. https://doi.org/10.1016/j.ejmech.2011.04.031
  10. Cheng, C.-C.; Chang, C.-P.; Yu, W.-S.; Hung, F.-T.; Liu, Y.-I.; Wu, G.-R.; Chou, P.-T. J. Phys. Chem. A 2003, 107, 1459. https://doi.org/10.1021/jp021243b
  11. Wang, X.; Zhi, B.; Baum, J.; Chen, Y.; Crockett, R.; Huang, L.; Eisenberg, S.; Larsen, J.; Ng, R.; Martinelli, M.; Reider, P. J. Org. Chem. 2006, 71, 4021. https://doi.org/10.1021/jo0602571
  12. Girgis, N. S.; Larson, S. B.; Robins, R. K.; Cottam, H. B. J. Heterocycl. Chem. 1989, 26, 317. https://doi.org/10.1002/jhet.5570260210
  13. El-Gamal, M. I.; Jung, M.-H.; Oh, C.-H. Bioorg. Med. Chem. Lett. 2010, 20, 3216. https://doi.org/10.1016/j.bmcl.2010.04.088
  14. NCI web site, www.dtp.nci.nih.gov.
  15. George, P. D. C.; Sudandiradoss, C.; Rajasekaran, R.; Purohit, R.; Ramanathan, K.; Sethumadhavan, R. J. Biomed. Inform. 2008, 41, 607. https://doi.org/10.1016/j.jbi.2007.12.004
  16. Chiarle, R.; Voena, C.; Ambrogio, C.; Piva, R.; Inghirami, G. Nat. Rev. Cancer 2008, 8, 11. https://doi.org/10.1038/nrc2291
  17. Cheng, M.; Ott, G. R. Anti-cancer Agents Med. Chem. 2010, 10, 236. https://doi.org/10.2174/1871520611009030236
  18. Elenitoba-Johnson, K. S. J.; Crockett, D. K.; Schumacher, J. A.; Jenson, S. D.; Cofn, C. M.; Rockwood, A. L.; Lim, M. S. Proc. Natl. Acad. Sci. U. S. A. 2006, 103, 7402. https://doi.org/10.1073/pnas.0506514103
  19. Soda, M.; Choi, Y. L.; Enomoto, M.; Takada, S.; Yamashita, Y.; Ishikawa, S.; Fujiwara, S.-I.; Watanabe, H.; Kurashina, K.; Hatanaka, H.; Bando, M.; Ohno, S.; Ishikawa, Y.; Aburatani, H.; Niki, T.; Sohara, Y.; Sugiyama, Y.; Mano, H. Nature 2007, 448, 561. https://doi.org/10.1038/nature05945
  20. Koivunen, J. P.; Mermel, C.; Zejnullahu, K.; Murphy, C.; Lifshits, E.; Holmes, A. J.; Choi, H. G.; Kim, J.; Chiang, D.; Thomas, R.; Lee, J.; Richards, W. G.; Sugarbaker, D. J.; Ducko, C.; Lindeman, N.; Marcoux, J. P.; Engelman, J. A.; Gray, N. S.; Lee, C.; Meyerson, M.; Jaenne, P. A. Clin. Cancer Res. 2008, 14, 4275. https://doi.org/10.1158/1078-0432.CCR-08-0168
  21. Lu, K. V.; Jong, K. A.; Kim, G. Y.; Singh, J.; Dia, E. Q.; Yoshimoto, K.; Wang, M. Y.; Cloughesy, T. F.; Nelson, S. F.; Mischel, P. S. J. Biol. Chem. 2005, 280, 26953. https://doi.org/10.1074/jbc.M502614200
  22. George, R. E.; Sanda, T.; Hanna, M.; Froehling, S.; Luther, W., II; Zhang, J.; Ahn, Y.; Zhou, W.; London, W. B.; McGrady, P.; Xue, L.; Zozulya, S.; Gregor, V. E.; Webb, T. R.; Gray, N. S.; Gilliland, D. G.; Diller, L.; Greulich, H.; Morris, S. W.; Meyerson, M.; Look, A. Nature 2008, 455, 975. https://doi.org/10.1038/nature07397
  23. Kolch, W.; Kotwaliwale, A.; Vass, K.; Janosch, P. Expert. Rev. Mol. Med. 2002, 4, 1.
  24. Dumaz, N.; Hayward, R.; Martin, J.; Ogilvie, L.; Hedley, D.; Curtin, J. A.; Bastian, B. C.; Springer, C.; Marais, R. Cancer Res. 2006, 66, 9483. https://doi.org/10.1158/0008-5472.CAN-05-4227
  25. Jilaveanu, L.; Zito, C. R.; Aziz, S. A.; Conrad, P. J.; Schmitz, J. C.; Sznol, M.; Camp, R. L.; Rimm, D. L.; Kluger, H. M. Clin. Cancer Res. 2009, 15, 5704. https://doi.org/10.1158/1078-0432.CCR-09-0198
  26. Smalley, K. S. M.; Xiao, M.; Villaneva, J.; Nguyen, T. K.; Flaherty, K. T.; Letrero, R.; Van Belle, P.; Elder, D. E.; Wang, Y.; Nathanson, K. L.; Herlyn, M. Oncogene 2009, 28, 85. https://doi.org/10.1038/onc.2008.362
  27. Davies, H.; Bignell, G. R.; Cox, C.; Stephens, P. Nature 2002, 417, 949. https://doi.org/10.1038/nature00766
  28. Tuveson, D. A.; Weber, B. L.; Herlyn, M. Cancer Cell 2003, 2, 95.
  29. Schmidt-Arras, D.; Schwäble, J.; Böhmer, F. D.; Serve, H. Curr. Pharm. Des. 2004, 10, 1867. https://doi.org/10.2174/1381612043384394
  30. Neuchrist, C.; Erovic, B. M.; Handisurya, A.; Steiner, G. E.; Rockwell, P.; Gedlicka, C.; Burian, M. Laryngoscope 2001, 111, 1834. https://doi.org/10.1097/00005537-200110000-00031
  31. Brodeur, G. M. Nat. Rev. Cancer 2003, 3, 203. https://doi.org/10.1038/nrc1014
  32. Schramm, A.; Schulte, J. H.; Astrahantseff, K.; Apostolov, O.; van Limpt, V.; Sieverts, H.; Kuhttig-Kulle, S.; Pfeiffer, P.; Versteeg, R.; Eggert, A. Cancer Lett. 2005, 228, 143. https://doi.org/10.1016/j.canlet.2005.02.051
  33. Thiele, C. J.; Li, Z. J.; Mckee, A. E.; Clin. Cancer Res. 2009, 15, 5962. https://doi.org/10.1158/1078-0432.CCR-08-0651
  34. Brodeur, G. M.; Minturn, J. E.; Ho, R.; Simpson, A. M.; Iyer, R.; Varela, C. R.; Light, J. E.; Kolla, V.; Evans, A. E. Clin. Cancer Res. 2009, 15, 3244. https://doi.org/10.1158/1078-0432.CCR-08-1815
  35. Siu, M. K. Y.; Wong, O. G. W.; Cheung, A. N. Y. Expert Opin. Ther. Targets 2009, 13, 1169. https://doi.org/10.1517/14728220903196787
  36. Au, C. W.; Siu, M. K.; Liao, X.; Wong, E. S.; Ngan, H. Y.; Tam, K. F.; Chan, D. C.; Chan, Q. K.; Cheung, A. N. Cancer Lett. 2009, 281, 151. https://doi.org/10.1016/j.canlet.2009.02.025
  37. Weeraratna, A. T.; Arnold, J. T.; George, D. J.; DeMarzo, A.; Isaacs, J. T. Prostate 2000, 45, 140. https://doi.org/10.1002/1097-0045(20001001)45:2<140::AID-PROS8>3.0.CO;2-#
  38. Yu, Y.; Zhang, S.; Wang, X.; Yang, Z.; Ou, G. APMIS 2010, 118, 188. https://doi.org/10.1111/j.1600-0463.2009.02577.x
  39. Vepsalainen, S.; Castren, E.; Helisalmi, S.; Iivonen, S.; Mannermaa, A.; Lehtovirta, M.; Hanninen, T.; Soininen, H.; Hiltunen, M. J. Neurol. 2005, 252, 423. https://doi.org/10.1007/s00415-005-0667-5
  40. Schindowski, K.; Belarbi, K.; Buee, L. Genes Brain Behav. 2008, 7(Suppl. 1), 43. https://doi.org/10.1111/j.1601-183X.2007.00378.x
  41. Gautschi, O.; Heighway, J.; Mack, P. C.; Purnell, P. R.; Lara, P. N., Jr.; Gandara, D. R. Clin. Cancer Res. 2008, 14, 1639. https://doi.org/10.1158/1078-0432.CCR-07-2179
  42. http://www.reactionbiology.com.

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