Tubulin-binding Dibenz[c,e]oxepines as Colchinol analogues for
targeting tumour vasculature

Edwards, David J; Hadfield, John A; Wallace, Timothy W; Ducki, Sylvie

Abstract

Various methoxy- and hydroxy-substituted dibenz[c,e]oxepines were prepared via the
copper(I)-induced coupling of ether-tethered arylstannanes or the dehydrative cyclisation of 1,1'-
biphenyl-2,2'-dimethanols, assembled using the Ullmann cross-coupling of ortho-bromoaryl carbonyl
compounds. The dibenzoxepines were screened for their ability to inhibit tubulin polymerisation and
the in vitro growth of K562 human chronic myelogenous leukemia cells. The most active was 5,7-
dihydro-3,9,10,11-tetramethoxybenz[c,e]oxepin-4-ol, whose tubulin inhibitory and cytotoxicity (IC50)
values were 1 μM and 40 nM respectively.

Citation

targeting tumour vasculature. Organic and Biomolecular Chemistry, 9(1), 219-231. https://doi.org/10.1039/c0ob00500b

• Journal Article Type: Article
• Acceptance Date: Oct 12, 2010
• Online Publication Date: Nov 17, 2010
• Publication Date: Jan 7, 2011
• Deposit Date: Nov 26, 2010
• Journal: Organic and Biomolecular Chemistry
• Print ISSN: 1477-0520
• Publisher: Royal Society of Chemistry
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Issue: 1
• Pages: 219-231
• DOI: https://doi.org/10.1039/c0ob00500b
• Publisher URL: http://dx.doi.org/10.1039/c0ob00500b
• Additional Information: References : 1. (a) N. Ferrara, H.-P. Gerber and J. LeCouter, Nat. Med., 2003, 9, 669–676; (b) D. Ribattia, A. Vaccab and M. Presta, Gen. Pharmacol., 2002, 35, 227–231. 2. (a) K. J. Kim, B. Li, J. Winer, M. Armanini, N. Gillett, H. S. Phillips and N. Ferrara, Nature, 1993, 362, 841–844; (b) L. G. Presta, H. Chen, H., S. J. O'Connor, V. Chisholm, Y. G. Meng, L. Krummen, M. Winkler and N. Ferrara, Cancer Res., 1997, 57, 4593–4599; (c) N. Ferrara, K. J. Hillan, H.-P. Gerber and W. Novotny, Nat. Rev. Drug Discovery, 2004, 3, 391–400. 3. For pertinent discussions, see (a) P. Carmeliet and R. K. Jain, Nature, 2000, 407, 249–257; (b) G. M. Tozer, Brit. J. Radiol., 2003, 76, S23-S35; (c) R. K. Jain, Science, 2005, 307, 58–62; (d) S. Yano, Y. Matsumori, K. Ikuta, H. Ogino, T. Doljinsuren and S. Sone, Int. J. Clin. Oncol., 2006, 11, 73–81; (e) S. Cébe- Suarez, A. Zehnder-Fjällman and K. Ballmer-Hofer, Cell. Mol. Life Sci., 2006, 63, 601–615; (f) A. Bozec, S. Lassalle, J. Gugenheim, J.-L. Fischel, P. Formento, P. Hofman and G. Milano, Br. J. Cancer, 2006, 95, 722–728; (g) L. M. Ellis and D. J. Hicklin, Nat. Rev. Cancer, 2008, 8, 579–591; (h) J. M. L. Roodhart, M. H. G. Langenberg, L. G. M. Daenen and E. E. Voest, Biochim. Biophys. Acta, Rev. Cancer, 2009, 1796, 41–49. 4. For reviews, see (a) P. E. Thorpe, Clin. Cancer Res., 2004, 10, 415–427; (b) G. M. Tozer, C. Kanthou and B. C. Baguley, Nature Rev. Cancer, 2005, 5, 423– 435; (c) C. Kanthou and G. M. Tozer, Int. J. Exp. Path., 2009, 90, 284–294. 5. J. W. Lippert, Bioorg. Med. Chem., 2007, 15, 605–615. 6. G. R. Pettit, S. B. Singh, M. R. Boyd, E. Hamel, R. K. Pettit, J. M. Schmidt and F. Hogan, J. Med. Chem. 1995, 38, 1666–1672, and references cited therein. 7. (a) G. G. Dark, S. A. Hill, V. E. Prise, G. M. Tozer, G. R. Pettit and D. J. Chaplin, Cancer Res., 1997, 57, 1829–1834; (b) S. M. Galbraith, R. J. Maxwell, M. A. Lodge, G. M. Tozer, J. Wilson, N. J. Taylor, J. J. Stirling, L. Sena, A. R. Padhani and G. S. Rustin, J. Clin. Oncol., 2003, 15, 2831–2842. Org. Biomol. Chem., doi: 10.1039/c0ob00500b (RSC COPYRIGHT) 27 8. (a) I. G. Kirwan, P. M. Loadman, D. J. Swaine, D. A. Anthoney, G. R. Pettit, J. W. Lippert, S. D. Shnyder, P. A. Cooper and M. C. Bibby, Clin. Cancer Res., 2004, 10, 1446–1453; (b) Y. Sheng, J. Hua, K. G. Pinney, C. M. Garner, R. R. Kane, J. A. Prezioso, D. J. Chaplin and K. Edvardsen, Int. J. Cancer, 2004, 111, 604–610; (c) H. W. Salmon and D. W. Siemann, Cancer Res., 2006, 12, 4090– 4094; (d) G. R. Pettit, A. J. Thornhill, B. R. Moser and F. Hogan, J. Nat. Prod., 2008, 71, 1561–1563. 9. (a) K. Hori, S. Saito and K. Kubota, Br. J. Cancer, 2002, 86, 1604–1614; (b) K. Hori and S. Saito, Br. J. Cancer, 2003, 89, 1334–1344; (c) A. Delmonte and C. Sessa, Expert Opin. Investig. Drugs, 2009, 18, 1541–1548. 10. (a) K. Miyazaki, M. Kobayashi, T. Natsume, M. Gondo, T. Mikami, K.Sakakibara and S. Tsukagoshi, Chem. Pharm. Bull., 1995, 43, 1706–1718; (b) N. Yamamoto, M. Andoh, M. Kawahara, M. Fukuoka and H. Niitani, Cancer Sci. 2009, 100, 316–321 and references cited therein. 11. (a) G. J. S. Rustin, C. Bradley, S. Galbraith, M. Stratford, P. Loadman, S. Waller, K. Bellenger, L. Gumbrell, L. Folkes and G. Halbert, Br. J. Cancer, 2003, 88, 1160–1167; (b) M. B. Jameson, P. I. Thompson, B. C. Baguley, B. D. Evans, V. J. Harvey, D. J. Porter, M. R. McCrystal, M. Small, K. Bellenger, L. Gumbrell, G. W. Halbert and P. Kestell, Br. J. Cancer, 2003, 88, 1844–1850; (c) B. G. Siim, A. E. Lee, S. Shalal-Zwain, F. B. Pruijn, M. J. McKeage and W. R. Wilson, Cancer Chemother. Pharmacol., 2003, 51, 43–52. 12. (a) S. Kasibhatla, V. Baichwal, S. X. Cai, B. Roth, I. Skvortsova, S. Skvortsov, P. Lukas, N. M. English, N. Sirisoma, J. Drewe, A. Pervin, B. Tseng, R. O. Carlson and C. M. Pleiman, Cancer Res., 2007, 67, 5865–5871; (b) N. Sirisoma, A. Pervin, H. Zhang, S. Jiang, J. A. Willardsen, M. B. Anderson, G. Mather, C. M. Pleiman, S. Kasibhatla, B. Tseng, J. Drewe and S. X. Cai, J. Med. Chem., 2009, 52, 2341–2351; (c) N. Sirisoma, A. Pervin, H. Zhang, S. Jiang, J. A. Willardsen, M. B. Anderson, G. Mather, C. M. Pleiman, S. Kasibhatla, B. Tseng, J. Drewe and S. X. Cai, Bioorg. Med. Chem. Lett., 2010, 20, 2330–2334. 13. (a) J. A. Segreti, J. S. Polakowski, K. A. Koch, K. C. Marsh, J. L. Bauch, S. H. Rosenberg, H. L. Sham, B. F. Cox and G. A. Reinhart, Cancer Chemother. Pharmacol., 2004, 54, 273–281; (b) Y. Luo, V. P. Hradil, D. J. Frost, S. H. Rosenberg, G. B. Gordon, S. J. Morgan, G. D. Gagne, B. F. Cox, S. K. Tahir and G. B. Fox, Anti-Cancer Drugs, 2009, 20, 483–492. 14. B. Nicholson, G. K. Lloyd, B. R. Miller, M. A. Palladino, Y. Kiso, Y. Hayashi and S. T. C. Neuteboom, Anti-Cancer Drugs, 2006, 17, 25–31. Org. Biomol. Chem., doi: 10.1039/c0ob00500b (RSC COPYRIGHT) 28 15. (a) W. Shi and D. W. Siemann, Anticancer Res., 2005, 25, 3899–3904; (b) A. M. Traynor, M. S. Gordon, D. Alberti, D. S. Mendelson, M. S. Munsey, G. Wilding, R. E. Gammans and W. L. Read, Invest. New Drugs, 2010, 28, 509– 515. 16. (a) S. Kasibhatla, H. Gourdeau, K. Meerovitch, J. Drewe, S. Reddy, L. Qiu, H. Zhang, F. Bergeron, D. Bouffard, Q. Yang, J. Herich, S. Lamothe, S. X. Cai and B. Tseng, Mol. Cancer Ther., 2004, 3, 1365–1373; (b) H. Gourdeau, L. Leblond, B. Hamelin, C. Desputeau, K. Dong, I. Kianicka, D. Custeau, C. Boudreau, L. Geerts, S.-X. Cai, J. Drewe, D. Labrecque, S. Kasibhatla and B. Tseng, Mol. Cancer Ther., 2004, 3, 1375–1383; (c) W. Kemnitzer, J. Drewe, S. Jiang, H. Zhang, Y. Wang, J. Zhao, S. Jia, J. Herich, D. Labreque, R. Storer, K. Meerovitch, D. Bouffard, R. Rej, R. Denis, C. Blais, S. Lamothe, G. Attardo, H. Gourdeau, B. Tseng, S. Kasibhatla and S. X. Cai, J. Med. Chem., 2004, 47, 6299–6310. 17. G. Kremmidiotis, A. F. Leske, T. C. Lavranos, D. Beaumont, J. Gasic, A. Hall, M. O'Callaghan, C. A. Matthews and B. Flynn, Mol. Cancer Ther., 2010, 9, 1562–1573. 18. (a) P. D. Davis, G. J. Dougherty, D. C. Blakey, S. M. Galbraith, G. M. Tozer, A. L. Holder, M. A. Naylor, J. Nolan, M. R. Stratford, D. J. Chaplin and S. A. Hill, Cancer Res., 2002, 62, 7247–7253; (b) D. C. Blakey, F. R. Westwood, M. Walker, G. D. Hughes, P. D. Davis, S. E. Ashton and A. J. Ryan, Clin. Cancer Res., 2002, 8, 1974–1983; (c) L. V. Beerepoot, S. A. Radema, E. O. Witteveen, T. Thomas, C. Wheeler, S. Kempin and E. E. Voest, J. Clin. Oncol., 2006, 24, 1491–1498; (d) S. Gould, F. R. Westwood, J. O. Curwen, S. E. Ashton, D. W. Roberts, S. C. Lovick and A. J. J. Natl. Cancer Inst., 2007, 99, 1724–1728. 19. (a) Z. J. Roberts, N. Goutagny, P.-Y. Perera, H. Kato, H. Kumar, T. Kawai, S. Akira, R. Savan, D. van Echo, K. A. Fitzgerald, H. A. Young, L.-M. Ching and S. N. Vogel, J. Exp. Med., 2007, 204, 1559–1569; (b) A. Wallace, D. F. LaRosa, V. Kapoor, J. Sun, G. Cheng, A. Jassar, A. Blouin, L.-M. Ching and S. M. Albelda, Cancer Res., 2007, 67, 7011–7019; (c) S. Gobbi, F. Belluti, A. Bisi, L. Piazzi, A. Rampa, A. Zampiron, M. Barbera, A. Caputo and M. Carrara, Bioorg. Med. Chem., 2006, 14, 4101–4109. 20. L.-M. Ching, Z. Cao, C. Kieda, S. Zwain, M. B. Jameson and B. C. Baguley, Br. J Cancer, 2002, 86, 1937–1942. 21. For reviews, see (a) K. H. Downing, Annu. Rev. Cell Dev. Biol., 2000, 16, 89– 111; (b) L. A. Amos, Org. Biomol. Chem., 2004, 2, 2153–2160. 22. (a) M. A. Jordan, R. J. Toso, D. Thrower and L. Wilson, Proc. Natl. Acad. Sci. USA, 1993, 90, 9552–9556 and references cited therein; (b) C. Elie-Caille, F. Org. Biomol. Chem., doi: 10.1039/c0ob00500b (RSC COPYRIGHT) 29 Severin, J. Helenius, J. Howard, D. J. Muller and A.A. Hyman, Curr. Biol., 2007, 17, 1765–1770; (c) S. Goodin, M. P. Kane and E. H. Rubin, J. Clin. Oncol., 2004, 22, 2015–2025. 23. B. Bhattacharyya, D. Panda, S. Gupta and M. Banerjee, Med. Res. Rev., 2008, 28, 155–183. 24. R. B. G. Ravelli, B. Gigant, P. A. Curmi, I. Jourdain, S. Lachkar, A. Sobel and M. Knossow, Nature, 2004, 428, 198–202. 25. (a) B. Gigant, C. Wang, R. B. G. Ravelli, F. Roussi, M. O. Steinmetz, P. A. Curmi, A. Sobel and M. Knossow, Nature, 2005, 435, 519–522; (b) A. Dorléans, B. Gigant, R. B. G. Ravelli, P. Mailliet, V. Mikol and M. Knossow, Proc. Natl. Acad. Sci. USA, 2009, 106, 13775–13779. 26. S. M. Galbraith, D. J. Chaplin, F. Lee, M. R. L. Stratford, R. J. Locke, B. Vojnovic and G. M. Tozer, Anticancer Res., 2001, 21, 93–102. 27. (a) C. M. Lin, S. B. Singh, P. S. Chu, R. O. Dempcy, J. M. Schmidt, G. R. Pettit and E. Hamel, Mol. Pharmacol., 1988, 34, 200–208; (b) C. M. Lin, H. H. Ho, G. R. Pettit and E. Hamel, Biochemistry, 1989, 28, 6984–6991. 28. For a review, see B. Bhattacharyya, D. Panda, S. Gupta and M. Banerjee, Med. Res. Rev., 2008, 28, 155–183. 29. T. J. Lampidis, D. Kolonias, N. Savaraj and R. W. Rubin, Proc. Natl. Acad. Sci. USA, 1992, 89, 1256–1260. 30. (a) W. J. van Heeckeren, S. Bhakta, J. Ortiz, J. Duerk, M. M. Cooney, A. Dowlati, K. McCrae and S. C. Remick, J. Clin. Oncol., 2006, 24, 1485–1488; (b) S. Gould, F. R. Westwood, J. O. Curwen, S. E. Ashton, D. W. Roberts, S. C. Lovick and A. J. Ryan, J. Natl. Cancer Inst., 2007, 99, 1724–1728; (c) For a study of the cardiovascular profile of CA-4P 2, see M. M. Cooney, T. Radivoyevitch, A. Dowlati, B. Overmoyer, N. Levitan, K. Robertson, S. L. Levine, K. DeCaro, C. Buchter, A. Taylor, B. S. Stambler and S. C. Remick, Clin. Cancer Res., 2004, 10, 96–100. 31. D. J. Edwards, R. G. Pritchard and T. W. Wallace, Acta Crystallogr., Sect. B: Struct. Sci., 2005, 61, 335–345. 32. T. W. Wallace, D. J. Edwards and J. A. Hadfield, PCT Int. Appl. WO 2008075048, 2008. 33. For independent studies along related lines, see (a) V. Colombel, A. Joncour, S. Thoret, J. Dubois, J. Bignon, J. Wdzieczak-Bakala and O. Baudoin, Tetrahedron Lett., 2010, 51, 3127–3129; (b) A. Joncour, J.-M. Liu, A. Décor, S. Thoret, J. Wdzieczak-Bakala, J. Bignon and O. Baudoin, ChemMedChem, 2008, 3, 1731–1739; (c) A. Joncour, A. Décor, S. Thoret, A. Chiaroni and O. Baudoin, Org. Biomol. Chem., doi: 10.1039/c0ob00500b (RSC COPYRIGHT) 30 Angew. Chem. Int. Ed., 2006, 45, 4149–4152; (d) N. Nicolaus, S. Strauss, J.-M. Neudörfl, A. Prokop and H.-G. Schmalz, Org. Lett., 2009, 11, 341–344. 34. E. Piers, J. G. K. Yee and P. L. Gladstone, Org. Lett., 2000, 2, 481–484. 35. H. Imanieh, P. Quayle, M. Voaden, J. Conway and S. D. A. Street, Tetrahedron Lett., 1992, 33, 543–546. 36. J. P. Deville and V. Behar, J. Org. Chem., 2001, 66, 4097–4098. 37. For reviews, see (a) T. D. Nelson and R. D. Crouch, Org. React., 2004, 63, 265–555; (b) J. Hassan, M. Sévignon, C. Gozzi, E. Schulz and M. Lemaire, Chem. Rev., 2002, 102, 1359–1469; (c) P. E. Fanta, Synthesis, 1974, 9–21. 38. E. Brown, J.-P. Robin and R. Dhal, Tetrahedron, 1982, 38, 2569–2579. 39. H. Suzuki, T. Enya and Y. Hisamatsu, Synthesis, 1997, 1273–1276. 40. (a) F. E. Ziegler, I. Chliwner, K. W. Fowler, S. J. Kanfer, S. J. Kuo and N. D. Sinha, J. Am. Chem. Soc., 1980, 102, 790–798; (b) F. E. Ziegler, K. W. Fowler, W. B. Rodgers and R. T. Wester, Org. Synth., 1987, 65, 108–118. 41. J. M. Insole, J. Chem. Res. (S), 1990, 378–379, (M) 2831–2867. 42. (a) G. Wu, H.-F. Guo, K. Gao, Y.-N. Liu, K. F. Bastow, S. L. Morris-Natschke, K.-H. Lee and L. Xie, Bioorg. Med. Chem. Lett., 2008, 18, 5272–5276; (b) L. G. Monovich, Y. Le Huérou, M. Rönn and G.A. Molander, J. Am. Chem. Soc., 2000, 122, 52–57. 43. I. Lantos and B. Loev, Tetrahedron Lett., 1975, 2011–2014. 44. M. Oki, H. Iwamura and T. Nishida, Bull. Chem. Soc. Jpn., 1968, 41, 656–660. 45. (a) N. J. Lawrence, A. T. McGown, S. Ducki and J. A. Hadfield, Anti-Cancer Drug Des., 2000, 15, 135–141; (b) J. A. Woods, J. A. Hadfield, G. R. Pettit, B. W. Fox and A. T. McGown, Br. J. Cancer, 1995, 71, 705–711. 46. (a) J. M. Edmondson, L. S. Armstrong and A. O. Martinez, J. Tissue Cult. Methods, 1988, 11, 15–17; (b) T. Mosmann, J. Immunol. Methods, 1983, 65, 55–63. 47. Y. Kataoka, M. Ishikawa, M. Miura, M. Takeshita, R. Fujita, S. Furusawa, M. Takayanagi, Y. Takayanagi and K. Sasaki, Biol. Pharm. Bull., 2001, 24, 612– 617. 48. O. Boye, A. Brossi, H. J. C. Yeh, E. Hamel, B. Wegrzynski and V. Toome, Can. J. Chem., 1992, 70, 1237–1249. 49. M. G. Banwell, J. M. Cameron, M. Corbett, J. R. Dupuche, E. Hamel, J. N. Lambert, C. M. Lin and M. F. Mackay, Aust. J. Chem., 1992, 45, 1967–1982. 50. S. Ducki, G. Mackenzie, B. Greedy, S. Armitage, J. Fournier Dit Chabert, E. Bennett, J. Nettles, J. P. Snyder and N. J. Lawrence, Bioorg. Med. Chem., 2009, 17, 7711–7722. Org. Biomol. Chem., doi: 10.1039/c0ob00500b (RSC COPYRIGHT) 31 51. For a discussion, see K. Mikami, K. Aikawa, Y. Yusa, J. J. Jodry and M. Yamanaka, Synlett, 2002, 1561–1578. 52. D. D. Perrin, W. L. F. Armarego and D. R. Perrin, Purification of Laboratory Chemicals, 2nd Edition, Pergamon, Oxford, 1980. 53. W. C. Still, M. Kahn and A. Mitra, J. Org. Chem., 1978, 43, 2923–2925. 54. N. Meyer and D. Seebach, Chem. Ber., 1980, 113, 1304–1319. 55. S. B. Singh and G. R. Pettit, Synth. Commun., 1987, 17, 877–892. 56. S. Mabic, L. Vaysse, C. Benezra and J.-P. Lepoittevin, Synthesis, 1999, 1127– 1134. 57. Y. Wang, C. A. Mathis, G. Huang, D. P. Holt, M. L. Debnath and W. E. Klunk, J. Labelled Compd. Radiopharm., 2002, 45, 647–664. 58. T. Takada, M. Arisawa, M. Gyoten, R. Hamada, H. Tohma and Y. Kita, J. Org. Chem., 1998, 63, 7698–7706. 59. D. A. Fletcher, R. F. McMeeking and D. Parkin, J. Chem. Inf. Comput. Sci., 1996, 36, 746–749