The Chemistry of Nitroimidazole Hypoxic Cell Radiosensitizers

  • C. E. Smithen
  • C. R. Hardy

Abstract

It is now well recognised that the imidazole ring system is an important component of many different types of natural products having a wide range of biological activities, including those essential for life itself. For example, in the form of the amino-acid L-histidine it is present in a variety of peptides, proteins and related macro-molecules and it fulfills an important functional role at the active sites of many different enzymes. The imidazole-1-β-riboside moiety, present in the purine nucleotides derived from adenine and guanine, forms an essential chiral building block in the macromolecular structure of the nucleic acids whilst other phosphate esters of the corresponding nucleosides, such as ATP, ADP and cyclic-AMP derived from adenosine, have vital functional roles in all living cells. The imidazole ring system is also found in various forms among low molecular weight natural products of animal, plant and microbial origin; either in simple form, as in the bio-amine histamine, or in much modified form, as in the vitamin biotin. One of the simplest of biologically active imidazoles is the antibiotic azomycin (I), first isolated in 1953 by the group of Umezawa1 and identified in 1955 by Nakamura2 as the hitherto unknown 2-nitroimidazole (Fig. 1).

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    K. Maeda, T. Osato and H. Umezawa, A new antibiotic, azomycin, J. Antibiotics (Tokyo), 6A:182 (1953).Google Scholar
  2. 2.
    S. Nakamura, Structure of azomycin, a new antibiotic, Pharm. Bull. (Tokyo), 3:379 (1955).Google Scholar
  3. 3.
    H. Horie, Antitrichomonas effect of azomycin, J. Antibiotics (Tokyo), 9A:168 (1956).Google Scholar
  4. 4.
    C. Cosar, C. Crisan, R. Horclois, R. M. Jacob, J. Robert, S. Tchelitcheff and R. Vaupre, Nitroimidazoles: preparation et activite chimiotherapeutique, Arzneimittel Forsch., 16:23 (1966).Google Scholar
  5. 5.
    B. Cavalleri, Nitroimidazole chemistry I. Synthetic methods, in Proc. Conf. on Nitroimidazoles, Cesenatico, Italy, (1980).Google Scholar
  6. 6.
    J. C. Asquith, J. L. Foster and R. L. Willson, Radiosensitization of hypoxic cells by metronidazole (Flagyl), Brit. J. Radiol., 46:648 (1973).PubMedCrossRefGoogle Scholar
  7. 7.
    J. C. Asquith, M. E. Watts, K. B. Patel, C. E. Smithen and G. E. Adams, Electron-affinic sensitization V. Radio-sensitization of hypoxic bacteria and mammalian cells in vitro by some nitroimidazoles and nitropyrazoles, Radiat. Res., 60:108 (1974).PubMedCrossRefGoogle Scholar
  8. 8.
    G. E. Adams, I. R. Flockhart, C. E. Smithen, I. J. Stratford, P. Wardman and M. E. Watts, Electron-affinic sensitization VII. A correlation between structures, one-electron reduction potentials and efficiences of nitroimidazoles as hypoxic cell radiosensitizers, Radiat. Res., 67:9 (1976).PubMedCrossRefGoogle Scholar
  9. 9.
    P. Wardman, The use of nitroaromatic compounds as hypoxic cell radiosensitizers, Curr. Topics Radiat. Res. Quart., 11:347 (1977).Google Scholar
  10. 10.
    G. E. Adams, E. D. Clarke, I. R. Flockhart, R. S. Jacobs, D. S. Sehmi, I. J. Stratford, P. Wardman, M. E. Watts, J. Parrick, R. G. Wallace and C. E. Smithen, Structure-activity relationships in the development of hypoxic cell radiosensitizers I. Sensitization efficiency, Int. J. Radiat. Biol., 35:133 (1979).CrossRefGoogle Scholar
  11. 11.
    G. E. Adams, I. Ahmed, E. D. Clarke, P. O’Neill, J. Parrick, I. J. Stratford, R. G. Wallace, P. Wardman and M. E. Watts, Structure-activity relationships in the development of hypoxic cell radiosensitizers III. Effects of basic substituents in nitroimidazole side-chains, Int. J. Radiat. Biol., 38:613 (1980).CrossRefGoogle Scholar
  12. 12.
    A. Breccia, Nitroimidazole chemistry II. Chemical properties and reaction mechanisms, in Proc. Conf. on Nitroimidazoles, Cesenatico, Italy (1980).Google Scholar
  13. 13.
    H. Monney, J. Parrick and R. G. Wallace, Nitroimidazole radiosensitizers: approaches to their chemical synthesis, Pharmacol. Therapeutics, in press (1981).Google Scholar
  14. 14.
    G. G. Gallo, C. R. Pasqualucci, P. Radaelli and G. C. Lancini, The ionization constants of some imidazoles, J. Org. Chem., 29:862 (1964).CrossRefGoogle Scholar
  15. 15.
    A. G. Beaman, W. Tautz, T. Gabriel, O. Keller, V. Toome and R. Duschinsky, Studies in the nitroimidazole series I. Synthesis of azomycin A and related compounds, Antimicrobial Agents and Chemotherapy 1965, 469 (1966).Google Scholar
  16. 16.
    R. J. Rousseau, R. K. Robins and L. B. Townsend, The synthesis of 2-nitro-1-β-D-ribofuranosylimidazole (azomycin riboside), J. Heterocyclic Chem., 4:311 (1967).CrossRefGoogle Scholar
  17. 17.
    J. L. Barascut, C. Tamby and J. L. Imbach, Synthetic nucleosides V. Ribofuranosides of some nitroazoles, J. Carbohydr., Nucleosides, Nucleotides, 1:77 (1974).Google Scholar
  18. 18.
    H. Guglielmi, Imidazole nucleosides II. Nucleosides of 4(5)-nitroimidazole-5(4)-carboxamide, Justus Liebigs Ann. Chem., 1286 (1973).Google Scholar
  19. 19.
    E. J. Prisbe, J. P. H. Verheyden and J. G. Moffatt, 5-Aza-7-deazapurine nucleosides 2. Synthesis of some 8-(D-ribo-furanosyl)imidazo[1,2-a]-1,3,5-triazine derivatives, J. Org. Chem., 43:4784 (1978).CrossRefGoogle Scholar
  20. 20.
    C. Chavis, F. Grodenic and J. L. Imbach, Nucleosides de synthèse XVII. Obtention de glycosyl-1-flitro-5-imidazoles et pyrazoles, Eur. J. Med. Chem., 14:123 (1979).Google Scholar
  21. 21.
    A. G. Beaman, W. Tautz and R. Duschinsky, Studies in the nitroimidazole series III. 2-Nitro imidazoles. substituted in the 1-position, Antimicrobial Agents and Chemotherapy 1967, 520 (1968).Google Scholar
  22. 22.
    A. G. Beaman and W. Tautz (F Hoffmann-La Roche &Co., Inc.), U. S. Patent 3,793,317 (1974).Google Scholar
  23. 23.
    A. G. Beaman (F Hoffmann-La Roche & Co., AG), U. K. Patent 1,066, 409 (1967).Google Scholar
  24. 24.
    C. E. Smithen (Roche Products Ltd.), U. K. Patent 2,003,154 (1979).Google Scholar
  25. 25.
    C. E. Smithen, unpublished data, Synthesis, chemistry and metabolism of misonidazole and closely related 2-nitro-imidazoles (Poster), presented at 6th Internat. Symposium on Medicinal Chemistry, Brighton, U. K. (1978).Google Scholar
  26. 26.
    G. C. Lancini, E. Lazzari, V. Ariole and P. Bellani, Synthesis and relationship between structure ana activity of 2-nitro-imidazole derivatives, J. Med. Chem., 12:775 (1969).PubMedCrossRefGoogle Scholar
  27. 27.
    A. Grimison and J. H. Ridd, The mechanisms of methylation of 4(5)-nitroglyoxaline with methyl sulphate, Chem. Industry, 983 (1956).Google Scholar
  28. 28.
    A. Grimison, J. H. Ridd and B. V. Smith, The mechanisms of N-substitution in glyoxaline derivatives I. Introduction and study of prototropic equilibria involving 4(5)-nitro-glyoxaline, J. Chem. Soc., 1352 (1960). II. The methylation of 4(5)-nitroglyoxaline by methyl sulphate, J. Chem. Soc., 1357 (1960).Google Scholar
  29. 29.
    J. H. Ridd and B. V. Smith, The mechanisms of N-substitution in glyoxaline derivatives III. Factors determining the orientation of N-methylation in substituted glyoxalines and benzimidazoles, J. Chem. Soc., 1363 (1960).Google Scholar
  30. 30.
    M. W. Miller, H. L. Howes, R. V. Kasubick and A. R. English, Alkylation of 2-methyl-5-nitroimidazoles: Some potent antiprotozoal agents, J. Med. Chem., 13:849 (1970).PubMedCrossRefGoogle Scholar
  31. 31.
    P. N. Giraldi, V. Mariotti, G. Nannini, G. P. Tosolini, E. Dradi, W. Logemann, I. de Cameri and G. Monti, Stucies on anti-protozoans II. Synthesis and biological activity of some N-alkylamino-nitroimidazoles, Arzneimittel-Forsch., 20:52 (1970).Google Scholar
  32. 32.
    F. Kajfez, V. Sunjic, D. Kolbah, T. Fajdiga and M. Oklobdzija, 1-Substitution in 2-methyl-4(5)-nitroimidazole I. Synthesis of compounds with potential antitrichomonal activity, J. Med. Chem., 11:167 (1968).PubMedCrossRefGoogle Scholar
  33. 33.
    K. Butler, H. L. Howes, J. E. Lynch and D. K. Pirie, Nitroimidazole derivatives: relationship between structure and antitrichomonal activity, J. Med. Chem., 10:891 (1967).PubMedCrossRefGoogle Scholar
  34. 34.
    M. Hoffer and E. Grunberg, Synthesis and antiprotozoal activity of l-(3-chloro-2-hydroxypropyl)-substituted nitroimidazoles, J. Med. Chem., 17:1019 (1974).PubMedCrossRefGoogle Scholar
  35. 35.
    V. Sunjic, D. Kolbah, F. Kajfez and N. Blazevic, 1-Imidazolyl derivatives of 2-hydroxy-3-phenoxypropane, J. Med. Chem., 11:1264 (1968).PubMedCrossRefGoogle Scholar
  36. 36.
    J. Suwinski, E. Salwinska, J. Watras and M. Widel, Synthesis and some physico-chemical properties of 1-(2-hydroxy-3-alkoxy-propyl)-4-nitroimidazoles (Polish), Acta Pol. Pharm., 35:529 (1978).PubMedGoogle Scholar
  37. 37.
    J. Suwinski, A. Rajca, J. Watras and M. Widel, Nitroimidazoles II. Synthesis and physico-chemical properties of N-sub-stituted 4 and 5-nitroimidazoles (Polish), Acta Pol. Pharm., 37:59 (1980).Google Scholar
  38. 38.
    J. Heeres, J. H. Mostmans, B. Maes and L. J. J. Backx, Synthesis and antiprotozoal activity of nitroimidazoles: carbamates and thiocarbamates, Eur. J. Med. Chem., 11:237 (1976).Google Scholar
  39. 39.
    K. C. Agrawal, K. B. Bears, R. K. Sehgal, J. N. Brown, P. E. Rist and W. D. Rupp, Potential radiosensitizing agents: dinitro-imidazoles, J. Med. Chem., 22:583 (1979).PubMedCrossRefGoogle Scholar
  40. 40.
    E. J. J. Grabowski, T. M. H. Iau, L. Salce and E. F. Schoenewaldt, An efficient and selective method for the synthesis of 2-(4-fluorophenyl)-1-(2-hydroxyethyl)-5-nitroimidazole (Flunidazole), J. Med. Chem., 17:547 (1974).PubMedCrossRefGoogle Scholar
  41. 41.
    E. Winkelmann, W. Raether, U. Gebert and A. Sinharay, Chemotherapeutically active nitro compounds IV. 5-Nitroimidazoles (Part 1), Arzneimittel-Forsch., 27:2251 (1977).Google Scholar
  42. 42.
    C. E. Smithen, E. D. Clarke, J. A. Dale, R. S. Jacobs, P. Wardman, M. E. Watts and M. Woodcock, Novel (nitro-1-imidazolyl)alkanolamines as potential radiosensitizers with improved therapeutic properties, in “Radiation Sensitizers: Their Use in the Clinical Management of Cancer”, L. W. Brady, ed., p. 22, Masson, New York (1980).Google Scholar
  43. 43.
    E. Gattavecchia and D. Tonelli, Thin-layer chromatography of some 5-nitroimidazoles of pharmaceutical interest, J. Chromatography, 193:340 (1980).CrossRefGoogle Scholar
  44. 44.
    A. G. Beaman, N. Caldwell, R. Duschinsky, N. J. Montclair and W. Tautz (F Hoffmann-La Roche & Co., AG), U. K. Patent 1,138,529 (1969).Google Scholar
  45. 45.
    J. M. Brown and W. W. Lee, Pharmacokinetic considerations in radiosensitizer development, in “Radiation Sensitizers: Their Use in the Clinical Management of Cancer”, L. W. Brady, ed., p. 2, Masson, New York (1980).Google Scholar
  46. 46.
    C. Rufer, H. J. Kessler and E. Schroeder, Chemotherapeutic nitroheterocycles VI. Substituted 5-aminomethyl-3-(5-nitrc-2-imidazolylmethylene)amino-2-oxazolidinones, J. Med. Chem., 14:94 (1971).PubMedCrossRefGoogle Scholar
  47. 47.
    G. E. Trout, Synthesis of some histidine analogs and their effect on the growth of a histidine-requiring mutant of Leuconostoc mesenteroides, J. Med. Chem., 15:1259 (1972).PubMedCrossRefGoogle Scholar
  48. 48.
    W. Tautz, S. Teitel and A. Brossi, Nitrohistidines and nitro-histamines, J. Med. Chem., 16:705 (1973).PubMedCrossRefGoogle Scholar
  49. 49.
    H. J. Kessler, C. Rufer and K. Schwarz, Chemotherapeutische nitroheterocyclen XXI. Synthese und antimikrobielle Eigenschaften der Enantiomeren von Furaltadon und einem analogen Nitroimidazolderivat (Moxnidazol), Eur. J, Med. Chem., 11:19 (1976).Google Scholar
  50. 50.
    W. Hofheinz, C. E. Smithen, P. Wardman and M. E. Watts, unpublished data (1980).Google Scholar
  51. 51.
    H. C. Beyerman, A. W. Buijen van Weelderen, L. Maat and A. Noordam, Imidazole chemistry II. Synthesis and chir-optical properties of (-)-(S)-2-chloro-3-(5-imidazolyl)-propanol, Rec. Trav. Chim., Pays-Bas, 91:216 (1972).Google Scholar
  52. 52.
    S. S. Berg and B. W. Sharp, Derivatives of 4- and 5-nitro-2-methylimidazolylacetaldehyde, Eur. J. Med. Chem., 10:171 (1975).Google Scholar
  53. 53.
    R. M. J. Ings, G. L. Law and E. W. Parnell, The metabolism of metronidazole (1–2’-hydroxyethyl-2-methyl-5-nitroimidazole), Biochem. Pharmacol., 15:515 (1966).PubMedCrossRefGoogle Scholar
  54. 54.
    P. N. Giraldi, G. P. Tosolini, E. Dradi, G. Nannini, R. Longo, G. Meinardi, G. Monti and I. de Carneri, Studies on anti-protozoans III. Isolation, identification and quantitative determination in humans of the metabolites of a new trichomonacidal agent, Biochem. Pharmacol., 20:339 (1971).PubMedCrossRefGoogle Scholar
  55. 55.
    M. J. Cho and J. J. Biermacher (Upjohn Co.), U. K. Patent 2,013,683 (1979).Google Scholar
  56. 56.
    A. G. Beaman (F Hoffmann-La Roche & Co. Inc.), U. S. Patent 3,468,902 (1969).Google Scholar
  57. 57.
    A. G. Beaman (F Hoffmann-La Roche & Co. Inc.), U. S. Patent 3,865,823 (1975).Google Scholar
  58. 58.
    P. Wardman, E. D. Clarke, R. S. Jacobs, A. Minchinton, M. R. L. Stratford, M. E. Watts, M. Woodcock, M. Moazzan, J. Parrick, R. G. Wallace and C. E. Smithen, Development of hypoxic cell radiosensitizers: the second and third generations, in “Radiation Sensitizers: Their Use in the Clinical Management of Cancer”, L. W. Brady, ed., p. 83, Masson, New York (1980).Google Scholar
  59. 59.
    A. W. Lutz and S. DeLorenzo, Novel halogenated imidazoles: chloroimidazoles, J. Heterocyclic Chem., 4:399 (1967).CrossRefGoogle Scholar
  60. 60.
    P. M. Kochergin, A. M. Tsyganova and V. S. Shlikhunova, Imidazoles XLIII. Synthesis of 4(5)-nitro-5(4)-brpmo-imidazoles (Russian), Khim. Farm. Zh., 2:22 (1968).Google Scholar
  61. 61.
    I. E. Balaban and F. L. Pyman, Bromo-derivatives of glyoxaline, J. Chem. Soc., 947 (1922).Google Scholar
  62. 62.
    P. M. Kochergin, Imidazole series XV. Reaction products of N,N’-dimethyloxamide with pentahalo-phosphorus compounds (Russian), Zh. Obshch. Khim., 34:3402 (1964).Google Scholar
  63. 63a.
    P. M. Kochergin, Imidazole series XVIII. 1-Alkyl or 1,2-di-alkyl-4-chloroimidazoles (Russian), Khim. Geterotsikl. Soedin., 754 (1965).Google Scholar
  64. 63b.
    Imidazole series XIX. Nitrochloroimidazoles (Russian), Khim. Geterotsikl. Soedin., 761 (1965).Google Scholar
  65. 64.
    J. Suwinski, E. Salwinska, J. Watras and M. Widel, Chloronitroimidazoles and 4,5-dinitroimidazoles: potential radio-sensitizers (Poster), Proc. Conf. on Nitroimidazoles, Cesenatico, Italy (1980).Google Scholar
  66. 65.
    M. Hoffer, V. Toome and A. Brossi, Nitroimidazoles II. Synthesis and reactions of iodonitroimidazoles. J. Heterocyclic Chem., 3:454 (1966).CrossRefGoogle Scholar
  67. 66.
    D. P. Davis, K. L. Kirk and L. A. Cohen, A new synthesis of 2-nitroimidazoles (Poster), Proc. Conf. on Nitroimidazoles, Cesenatico, Italy (1980).Google Scholar
  68. 67.
    K. L. Kirk, Facile synthesis of 2-substituted imidazoles, J. Org. Chem., 43:4381 (1978).CrossRefGoogle Scholar
  69. 68.
    G. B. Bariin, The relative electron-releasing power of a singly bound and the electron-attracting power of a doubly bound nitrogen atom when present in the same five-membered ring, J. Chem. Soc. (B), 641 (1967).Google Scholar
  70. 69.
    C. R. Hardy, unpublished data (1980).Google Scholar
  71. 70.
    V. Sunjic, T. Fajdiga, M. Japelj and P. Rems, Nucleophilic substitutions in some derivatives of 4- and 5-nitroimidazoles, J. Heterocyclic Chem., 6:53 (1969).CrossRefGoogle Scholar
  72. 71.
    V. Sunjic, T. Fajdiga and M. Japelj, Reactions of some 1-(carboxyalkyl)nitroimidazole derivatives in polyphosphoric acid, J. Heterocyclic Chem., 7:211 (1970).CrossRefGoogle Scholar
  73. 72.
    P. M. Kochergin, A. M. Tsyganova, V. S. Shlikhunova and M. A. Klykov, Imidazoles LVI. Nucleophilic substitution of 4(5)-nitro-5(4)-chloro or bromoimidazoles (Russian), Khim. Geterotsikl. Soedin., 7:689 (1971).Google Scholar
  74. 73.
    L. F. Miller and R. E. Bambury, 2-Amino-5-nitroimidazoles, J. Med. Chem., 14.1217 (1971).PubMedCrossRefGoogle Scholar
  75. 74.
    F. F. Blicke and C. M. Lee, Derivatives of 7-inethyl-6-thia-1,6-dihydro and 7-methyl-6-thia-1,2,3,6-tetrahydropurine-6,6-dioxide, J. Org. Chem., 26:1861 (1961).CrossRefGoogle Scholar
  76. 75.
    R. C. Tweit, E. M. Kreider and R. D. Muir, Synthesis of antimicrobial nitroimidazolyl 2-sulfides, sulfoxides and sulfones, J. Med. Chem., 16:1161 (1973).PubMedCrossRefGoogle Scholar
  77. 76.
    R. C. Tweit, R. D. Muir and S. Ziecina, Nitroimidazoles with antibacterial activity against Neisseria gonorrhoeae, J. Med. Chem., 20:1697 (1977).PubMedCrossRefGoogle Scholar
  78. 77.
    F. L. Pyman and G. M. Timmis, Bromo-derivatives of 4-methyl-glyoxaline, J. Chem. Soc., 494 (1923).Google Scholar
  79. 78.
    Merck & Co., Inc., Neth. Appl. 6,409,120 (1965).Google Scholar
  80. 79.
    E. C. Taylor and P. K. Loeffler, Studies in purine chemistry IX. A new pyrimidine synthesis from o-aminonitriles, J. Amer. Chem. Soc., 82:3147 (1960).CrossRefGoogle Scholar
  81. 80.
    J. Baddiley, J. G. Buchanan, F. E. Hardy and J. Stewart, Chemical studies in the biosynthesis of purine nucleotides III. The synthesis of 5-amino-1-(β-D-ribofuranosyl)glyoxa-line-4-carboxyamide and 4-amino-1-(β-D-ribofuranosyl)glyoxa-line-5-carboxyamide, J. Chem. Soc., 2893 (1959).Google Scholar
  82. 81.
    D. W. Henry (Merck & Co., Inc.), U. S. Patent 3,644,392 (1972).Google Scholar
  83. 82.
    L. L. Bennett and H. T. Baker, Synthesis of potential anticancer agents IV. 4-Nitro and 4-amino-5-imidazole sulfones, J. Amer. Chem. Soc., 79:2188 (1957).CrossRefGoogle Scholar
  84. 83.
    G. Asato and G. Berkelhammer, Nitroheterocyclic antimicrobial agents: 1-methyl-2-nitro-5-imidazolyl derivatives, J. Med. Chem., 15:1087 (1972).CrossRefGoogle Scholar
  85. 84.
    D. W. Henry and D. R. Hoff (Merck & Co., Inc.), Belg. Patent 661,262 (1965).Google Scholar
  86. 85.
    H. Hagen and R. D. Kohler (BASF AG.), Ger. Offen 2,827,351 (1980).Google Scholar
  87. 86.
    J. D. Albright and R. G. Shepherd, Reactions of 1,2-dimethyl-5-nitroimidazole: novel methods of conversion of the 2-methyl group to a nitrile, J. Heterocyclic Chem., 10:899 (1973).CrossRefGoogle Scholar
  88. 87.
    C. Rufer, K. Schwarz and E. Winterfeldt, Chemotherapeutic nitro-heterocycles XIX. Synthesis of 5-nitroimidazoles substituted in the 2-position by heterocycles, Justus Liebigs Ann. Chem., 1465 (1975).Google Scholar
  89. 88.
    P. B. Ayscough, A. J. Elliot and G. A. Salmon, In situ radio-lysis electron spin resonance study of the radical-anions of substituted nitroimidazoles and nitroaromatic compounds, J. Chem. Soc., 74:511 (1978).Google Scholar
  90. 89.
    E. Perez-Reyes, B. Kalyanaraman and R. P. Mason, The reductive metabolism of metronidazole and ronidazole by aerobic liver microsomes, Mol. Pharmacol., 17:239 (1980).PubMedGoogle Scholar
  91. 90.
    A. J. Varghese and G. F. Whitmore, Binding of nitroreduction products of misonidazole to nucleic acids and protein, in “Radiation Sensitizers: Their Use in the Clinical Management of Cancer”, L. W. Brady, ed., p. 57, Masson, New York (1980).Google Scholar
  92. 91.
    P. D. Josephy, B. Palcic and L. D. Skarsgard, Synthesis and properties of reduced derivatives of misonidazole, in “Radiation Sensitizers: Their Use in the Clinical Management of Cancer”, L. W. Brady, ed., p. 61, Masson, New York (1980).Google Scholar
  93. 92.
    R. C. Knight, D. A. Rowley, I. M. Skolimowski and D. I. Edwards, Mechanism of action of nitroimidazole antimicrobial and antitumour radiosensitizing drugs: effects of reduced misonidazole on DNA, Int. J. Radiat. Biol., 36:367 (1979).CrossRefGoogle Scholar
  94. 93.
    D. W. Whillans and G. F. Whitmore, The radiation chemical reduction of misonidazole (Abstract), Radiat. Res., 83:467 (1980).Google Scholar
  95. 94.
    E. D. Clarke, P. Wardman and K. H. Goulding, Anaerobic reduction of nitroimidazoles by reduced flavin mononucleotide and by xanthine oxidase, Biochem. Pharmacol., 29:2684 (1980).PubMedCrossRefGoogle Scholar
  96. 95.
    P. D. Josephy, B. Palcic and L. D. Skarsgard, Reduction of misonidazole and its derivatives by xanthine oxidase, Biochem. Pharmacol., 30:849 (1981).PubMedCrossRefGoogle Scholar
  97. 96.
    I. R. Flockhart, P. Large, D. Troup, S. L. Malcolm and T. R. Marten, Pharmacokinetics and metabolic studies of the hypoxic cell radiosensitizer misonidazole, Xenobiotica, 8:97 (1978).PubMedCrossRefGoogle Scholar
  98. 97.
    J. E. Stambaugh, L. G. Feo and R. W. Manthei, The isolation and identification of the urinary oxidative metabolites of metronidazole in man, J. Pharmacol. Exp. Ther., 161:373 (1968).PubMedGoogle Scholar
  99. 98.
    P. Goldman, R. L. Koch and E. J. T. Chrystal, Anaerobic metabolism of metronidazole and its consequences, in “Radiation Sensitizers: Their Use in the Clinical Management of Cancer”, L. W. Brady, ed., p. 225, Masson, New York (1980).Google Scholar
  100. 99.
    G. C. Lancini, N. Maggi and P. Sensi, Synthesis of some derivatives of 2-nitroimidazole with potential antitrichomonal activity, Farmaco, Ed. Sci., 18:390 (1963).Google Scholar
  101. 100.
    R. K. Sehgal and K. C. Agrawal, Hydroxymethylation and cyano-methylation of nitroimidazoles, J. Heterocyclic Chem., 16:871 (1979).CrossRefGoogle Scholar
  102. 101.
    C. Oldenhof and J. Cornelisse, Photoreactions of aromatic compounds XXXVI. Nucleophilic photosubstitution reactions of some derivatives of imidazole and pyrazole, Rec. Trav. Chim., Pays-Bas, 97:35 (1978).CrossRefGoogle Scholar
  103. 102.
    F. Kajfez, L. Klasinc and V. Sunjic, Application of photo-electron spectroscopy to biologically active molecules and their constituent parts IV. Methylnitroimidazoles, J. Heterocyclic Chem., 16:529 (1979).CrossRefGoogle Scholar
  104. 103.
    T. Matsuura and M. Ikari, Photoinduced reactions XXVII. Photosensitized oxygenation of alkylated imidazoles (Japanese), Kogyu KagaKu Zasshi, 72:179 (1969).CrossRefGoogle Scholar
  105. 104.
    D. E. Schwartz and W. Hofheinz, Metabolism of nitroimidazoles, in Proc. Conf. on Nitroimidazoles, Cesenatico, Italy (1980).Google Scholar
  106. 105.
    C. Rosenblum, N. R. Trenner, R. P. Buhs, C. B. Hiremath, F. R. Koniuszy and D. E. Wolf, Metabolism of ronidazole (1-methyl-5-nitroimidazol-2-ylmethylcarbamate), J. Agric. Food Chem., 20:360 (1972).PubMedCrossRefGoogle Scholar
  107. 106.
    G. Weiss, N. R. Felicito, P. D. Duke and T. Williams, The isolation of a major rat fecal metabolite of ipronidazole, Xenobiotica, in press (1981).Google Scholar
  108. 107.
    T. R. Marten, R. J. Ruane, J. A. White and L. Clarke, Pharmacokinetics of nitroimidazoles, in Proc. Conf. on Nitroimidazoles, Cesenatico, Italy (1980).Google Scholar
  109. 108.
    Our own studies of the chemistry of nitroimidazoles have been greatly facilitated by the advice and support of numerous colleagues at Roche, at CRC Gray Laboratory, Mount Vernon and at ICR Sutton.Google Scholar

Copyright information

© Plenum Press, New York 1982

Authors and Affiliations

  • C. E. Smithen
    • 1
    • 2
  • C. R. Hardy
    • 1
    • 2
  1. 1.Roche Products LimitedWelvyn Garden City, HertfordshireEngland
  2. 2.Institute of Cancer ResearchSutton, SurreyEngland

Personalised recommendations