5-Nitrofuran-2-ylmethyl group as a potential bioreductively activated pro-drug system

Abstract

5-Substituted isoquinolin-1-ones have been synthesised by one-pot Curtius rearrangement of the corresponding substituted 3-phenylpropenoyl azides and cyclisation. Arylmethylation of the anions of the isoquinolinones with benzyl halides [4-methoxybenzyl chloride, 2-(chloromethyl)furan and 5-nitro-2-(tosyloxymethyl)furan] takes place exclusively at nitrogen. Nitration of 2-(furan-2-ylmethyl)isoquinolin-1-one in strongly acidic medium gives 2-(5-nitrofuran-2-ylmethyl)isoquinolin-1-one, whereas weaker acidic conditions lead to dinitration. Curtius rearrangement of 3-carboranylbutanoyl azide and trapping with 5-nitrofuran-2-ylmethanol gives 5-nitrofuran-2-ylmethyl N-(3-carboranylpropyl)carbamate. Biomimetic reduction of these nitrofuranylmethyl derivatives of anticancer drugs triggers release of the parent drugs. Thus, these nitrofurans have potential applications as pro-drugs for selective release of therapeutic drugs in hypoxic solid tumours.

References

1. P. Vaupel, F. Kallinowski and P. Okunieff, Cancer Res., 1989, 49, 6449; P. Okunieff, M. Hoeckel, E. P. Dunphy, K. Schlenger, C. Knoop and P. Vaupel, Int. J. Radiat. Oncol. Biol. Phys., 1993, 26, 631.
2. K. A. Kennedy, B. A. Teicher, S. Rockwell and A. C. Sartorelli, Biochem. Pharmacol., 1980, 29, 1; S. R. Keyes, P. M. Fracasso, D. C. Heimbrook, S. Rockwell, S. G. Sligar and A. C. Sartorelli, Cancer Res., 1985, 45, 3642; M. A. Naylor, M. A. Stephens, S. Cole, M. D. Threadgill, I. J. Stratford, P. O'Neill, E. M. Fielden and G. E. Adams, J. Med. Chem., 1990, 33, 2508; T. C. Jenkins, M. A. Naylor, P. O'Neill, M. D. Threadgill, S. Cole, I. J. Stratford, G. E. Adams, E. M. Fielden, M. J. Suto and M. J. Steir, J. Med. Chem., 1990, 33, 2603; A. K. Sinhababu and D. R. Thakker, Adv. Drug Delivery Rev., 1996, 19, 241.
3. M. B. Parliament, J. D. Chapman, R. C. Urtasun, A. J. McEwan, L. Golberg, J. R. Mercer, R. H. Mannan and L. I. Wiebe, Br. J. Cancer, 1992, 65, 90; R. J. Maxwell, P. Workman and R. J. Griffiths, Int. J. Radiat. Oncol. Biol. Phys., 1989, 16, 925.
4. P. J. Wood, M. Scobie and M. D. Threadgill, Int. J. Radiat. Biol., 1996, 70, 587; D. H. Swenson, B. H. Laster and R. L. Metzger, J. Med. Chem., 1996, 39, 1540.
5. B. M. Sykes, G. J. Atwell, W. A. Denny and C. J. O'Connor, J. Phys. Org. Chem., 1995, 8, 587; B. M. Sykes, G. J. Atwell, W. A. Denny, D. J. McLennan and C. J. O'Connor, J. Chem. Soc., Perkin Trans. 2, 1995, 337.
6. A. B. Mauger, P. J. Burke, H. H. Somani, F. Friedlos and R. J. Knox, J. Med. Chem., 1994, 37, 3452; M. P. Hay, W. R. Wilson and W. A. Denny, Bioorg. Med. Chem. Lett., 1995, 5, 2829.
7. M. A. Naylor, M. A. Stephens, S. Cole, M. D. Threadgill, I. J. Stratford, P. O'Neill, E. M. Fielden and G. E. Adams, J. Med. Chem., 1990, 33, 2508.
8. P. Workman and I. J. Stratford, Cancer Metastasis Rev., 1993, 12, 73.
9. M. J. Suto, W. R. Turner, C. M. Arundel-Suto, L. M. Werbel and J. S. Sebolt-Leopold, Anti-Cancer Drug Des., 1991, 7, 107; C. M. Arundel-Suto, S. V. Scavone, W. R. Turner, M. J. Suto and J. S. Sebolt-Leopold, Radiat. Res., 1991, 126, 367.
10. I. R. Judson and M. D. Threadgill, Lancet, 1993, 342, 632; R. J. Griffin, L. C. Pemberton, D. Rhodes, C. Bleasdale, K. Bowman, N. J. Curtin, B. W. Durkacz, D. R. Newell, J. K. Porteous and B. T. Golding, Anti-Cancer Drug Des., 1995, 10, 507; R. J. Griffin, N. J. Curtin, D. R. Newell, B. T. Golding, B. W. Durkacz and A. H. Calvert, Biochimie, 1995, 77, 408.
11. M. F. Hawthorne, Angew. Chem., Int. Ed. Engl., 1993, 32, 950; R. F. Barth, A. H. Soloway and R. G. Fairchild, Cancer Res., 1990, 50, 1061; B. F. Spielvogel, A. Sood, B. F. Shaw and I. H. Shaw, Pure Appl. Chem., 1991, 63, 415; J. H. Morris, Chem. Br., 1991, 331.
12. A. H. Soloway, R. L. Wright and J. R. Messner, J. Pharmacol. Exp. Ther., 1961, 134, 117; H. Hatanaka, in Boron Neutron Capture Therapy for Tumors, ed. H. Hatanaka, Nishimura Co. Ltd., Niigata, 1986.
13. H. S. Wong, E. I. Tolpin and W. N. Lipscomb, J. Med. Chem., 1974, 17, 785.
14. Y. Yamamoto, T. Seko, H. Nakamura, H. Nemoto, H. Hojo, N. Nukai and Y. Hashimoto, J. Chem. Soc., Chem. Commun., 1992, 157; W. Tjarks, A. K. M. Anisuzzaman, L. Liu, A. H. Soloway, R. F. Barth, D. J. Perkins and D. M. Adams, J. Med. Chem., 1992, 35, 1628.
15. M. Miura, D. Gabel, G. Oenbrink and R. G. Fairchild, Tetrahedron Lett., 1992, 33, 7489.
16. M. Scobie, M. F. Mahon and M. D. Threadgill, J. Chem. Soc., Perkin Trans. 1, 1994, 203; M. Scobie, S. P. Bew and M. D. Threadgill, J. Labelled Compd. Radiopharm., 1994, 34, 881; M. Scobie and M. D. Threadgill, J. Org. Chem., 1994, 59, 7008.
17. M. Scobie and M. D. Threadgill, J. Chem. Soc., Perkin Trans. 1, 1994, 2059.
18. M. Berklava and S. Hilliers, Latv. PSR Zinat. Akad. Vestis, Kim. Ser., 1963, 349 (Chem. Abstr., 1964, 60, 1674g).
19. C.-T. Wang, C.-T. Chang and W.-C. Chen, K'o Hsueh T'ung Pao, 1959, 493 (Chem. Abstr., 1960, 54, 8773g).
20. M. M. Robison and B. L. Robison, J. Am. Chem. Soc., 1958, 80, 3443; E. Ochiai and Y. Kawazoe, Chem. Pharm. Bull., 1957, 5, 289; E. Ochiai and Y. Kawazoe, Chem. Pharm. Bull., 1960, 8, 24; H. Win and K. Koshinuma, J. Org. Chem., 1967, 32, 59.
21. M. M. Robison and B. L. Robison, J. Org. Chem., 1958, 23, 1071.
22. S. Ruchirawat, S. Sunkul, Y. Thebtaranonth and N. Thirasasna, Tetrahedron Lett., 1977, 2335; J. W. Bunting, P. A. Lee-Young and D. J. Norris, J. Org. Chem., 1978, 43, 1132; F. Kröhnke and I. Vogt, Liebigs Ann. Chem., 1956, 600, 211.
23. F. Eloy and A. Deryckere, Helv. Chim. Acta, 1969, 52, 1755.
24. J. Klein and E. D. Bergmann, J. Am. Chem. Soc., 1957, 79, 3452.
25. J. E. Plevyak, J. E. Dickerson and R. F. Heck, J. Org. Chem., 1979, 44, 4078.
26. L. W. Deady, W. L. Finlayson and C. H. Potts, Aust. J. Chem., 1977, 30, 1349; G. Tarrago, C. Marzin, O. Najimi and V. Pellegrin, J. Org. Chem., 1990, 55, 420; S. Kamiya and K. Koshinuma, Chem. Pharm. Bull., 1967, 15, 1985; K. T. Potts and S. Yao, J. Org. Chem., 1979, 44, 977; T. Matsui, T. Sugiura, H. Nakai, S. Iguchi, S. Shigeoka, H. Takada, Y. Odagaki, Y. Nagao, Y. Ushio, K. Ohmoto, H. Iwamura, S. Yamazaki, Y. Arai and M. Kawamura, J. Med. Chem., 1992, 35, 3307.
27. G. Tarrago, C. Marzin, O. Najimi and V. Pellegrin, J. Org. Chem., 1990, 55, 420.
28. D. E. Horning, G. Lacase and J. M. Muchowski, Can. J. Chem., 1971, 49, 2785.
29. Y. Kawazoe and Y. Yoshioka, Chem. Pharm. Bull., 1968, 16, 715.
30. V. I. Stanko and G. A. Anorova, Zh. Obshch. Khim., 1966, 36, 946; V. I. Stanko, G. A. Anorova and T. P. Klimova, Zh. Obshch. Khim., 1966, 36, 1774.
31. A. H. Soloway and D. N. Butler, J. Med. Chem., 1966, 9, 411.
32. T. Neilson, H. C. S. Wood and A. G. Wylie, J. Chem. Soc., 1962, 371.
33. J. S. Buck and W. S. Ide, Org. Synth., 1943, Coll. Vol. 2, 130.
34. R. F. Raffauf, J. Am. Chem. Soc., 1950, 72, 653.
35. H. Gilman and R. R. Burtner, Iowa State Coll. J. Sci., 1932, 6, 389 (Chem. Abstr., 1933, 27, 2888).
36. K. Y. Novitskii, G. T. Khachaturova and Y. K. Yur'ev, Zh. Obshch. Khim., 1964, 34, 1807.
37. G. E. Adams, E. M. Fielden, M. A. Naylor and I. J. Stratford, Canadian Patent 2092616, 1995(Chem. Abstr., 1955, 121, 134161).
38. W. S. Rapson and R. G. Shuttleworth, J. Chem. Soc., 1941, 487.
39. R. G. R. Bacon and W. S. Lindsay, J. Chem. Soc., 1958, 1375.
40. H. W. Post, J. Org. Chem., 1940, 5, 244.
41. S. Gabriel and M. Herzberg, Ber. Dtsch. Chem. Ges., 1883, 16, 2036.
42. W. Miersch, Ber. Dtsch. Chem. Ges., 1882, 25, 2109.
43. T. Izumi, Y. Nishimoto, K. Kohei and A. Kasahara, J. Heterocycl. Chem., 1990, 27, 1419.
44. M. Noguchi, S. Kakimoto, H. Kawakami and S. Kajigaeshi, Bull. Chem. Soc. Jpn., 1986, 59, 1355.
45. J. M. Berry and M. D. Threadgill, J. Labelled Compd. Radiopharm., 1996, 38, 935; J. M. Berry and M. D. Threadgill, J. Labelled Compd. Radiopharm., in the press.
46. R. J. Ferrier and J. M. Tedder, J. Chem. Soc., 1957, 1435.
47. J. A. Gaultier, M. Miocque and L. Mascrier-Demagny, C. R. Acad. Sci., 1961, 253, 1971.
48. L. I. Zakharkin, Y. A. Chapovskii, V. A. Brathev and V. I. Stanko, Zh. Obshch. Khim., 1966, 36, 878.