The mitomycins were first obtained in 1956 from Streptomyces caespitosus by Hata and coworkers in Japan (1, 2). The isolation involved alumina chromatography of the chloroform extracts of the concentrated aqueous filtrates of the fermentation broth. Although there were many active components in the eluted fractions, only two antibiotics, mitomycins A and B were obtained in crystalline form. Later fractionations of broths of S. caespitosus yielded mitomycin C (3). By 1958, the outstanding antitumor activity of mitomycin C was a subject of great interest in spite of the fact that there existed no firm evidence as to its structure (4). In 1960, N-methylmitomycin C, called porfiromycin, was isolated from cultures of Streptoverticillatium ardus (5). In 1962 the isolation of the same four antibiotics from Streptomyces verticillatus was reported in the U.S. (6). Additionally, a fifth, but inactive member of mitomycin family, mitiromycin was obtained. The fractionation of the S. verticillatus broths to afford the crystalline antibiotics was accomplished by partition chromatography on a diatomaceous earth support.


Pyruvic Acid Synthetic Study Quinone Methide Antitumor Antibiotic Diatomaceous Earth Support 
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  1. 1.
    Hata, T., Y. Sano, R. Sugawara, A. Matsumae, K. Kanamori, T. Shima, and T. Hoshi: Mitomycin, a New Antibiotic from Streptomyces. I. J. Antibiotics, Ser. A. 9, 141 (1956).Google Scholar
  2. 2.
    Sugawara, R., and T. Hata: Mitomycin, a New Antibiotic from Streptomyces. II. Description of the strain. J. Antibiotics, Ser. A. 9, 147 (1956).Google Scholar
  3. 3.
    Wakagi, S., H. Marumo, K. Tomoka, G. Shimizu, E. Kato, H. Kamada, S. Kudo, and Y. Fujimoto: Isolation of News Fractions of Antitumor Mitomycins. Antibiot. and Chemoth. 8, 228 (1958).Google Scholar
  4. 4.
    Wakagi, S.: Identification and Classification of Antitumor Mitomycin Group. Gann. 49 (Suppl.), 10 (1958).Google Scholar
  5. 5.
    Herr, R. R., M. E. Bergy, T. E. Eble, and H. K. Jahnke: Porfiromycin, a New Antibiotic. II. Isolation and Characterization. Antimicrobial Agents Ann. 1960, 23 (1961).Google Scholar
  6. 6.
    Lefemine, D. V., M. Dann, F. Barbatschi, W. K. Hausmann, V. Zbinovsky, P. Monnikendam, J. Adam, and N. Bohonos: Isolation and Characterization of Mitiromycin and Other Antibiotics Produced by Streptomyces Verticillatus. J. Amer. Chem. Soc. 84, 3184 (1962).CrossRefGoogle Scholar
  7. 7.
    Uzu, K., Y. Harada, and S. Wakaki: Mitomycins, Carcinostatic Antibiotics. I. Derivatives and Acid Hydrolysis of Mitomycin A and C. Agr. Biol. Chem. 28, 388 (1964).Google Scholar
  8. 8.
    Uzu, K., Y. Harada, S. Wakaki, and Y. Yamada: Mitomycins, Carcinostatic Antibiotics. II. Mitomycinone. Agr. Biol. Chem. 28, 394 (1964).CrossRefGoogle Scholar
  9. 9.
    Webb, J. S., D. B. Cosulich, J. H. Mowat, J. B. Patrick, R. W. Broschard, W. E. Meyer, R. P. Williams, C. F. Wolf, W. Fulmor, C. Pidacks, and J. E. Lancaster: The Structures of Mitomycins A, B, and C and Porfiromycin-Parts I and II. J. Amer. Chem. Soc. 84, 3185 (1962).CrossRefGoogle Scholar
  10. 10.
    Stevens, C. L., K. G. Taylor, M. E. Munk, W. S. Marshall, K. Noll, G. D. Shah, L. G. Shah, and K. Uzu: Chemistry and Structure of Mitomycin C. J. Med. Chem. 8, 1 (1965).CrossRefGoogle Scholar
  11. 11.
    Tulinsky, A.: The Structure of Mitomycin A. J. Amer. Chem. Soc. 84, 3188 (1962).CrossRefGoogle Scholar
  12. 12.
    Tulinsky, A., and J. H. Van Den Hende: The Crystal and Molecular Structure of N-Brosylmitomycin A. J. Amer. Chem. Soc. 89, 2905 (1967).CrossRefGoogle Scholar
  13. 13.
    Yahashi, R., and I. Matsubara: The Molecular Structure of 7-Demethoxy-7-p-bromoanilinomitomycin B. J. Antibiotics 29, 104 (1976).Google Scholar
  14. 14.
    Webb, J. S.: Private Communication.Google Scholar
  15. 15.
    Lown, J. W., and A. Begleiter: Studies Relating to Aziridine Antitumor Antibiotics. Part II. 13 and 1H Nuclear Magnetic Resonance Spectra of Mitomycin C and Structurally Related Streptonigrin. Canad. J. Chem. 52, 2331 (1974).CrossRefGoogle Scholar
  16. 16.
    Van Lear, G.: Mass Spectrometric Studies of Antibiotics — I. Mass Spectra of Mitomycin Antibiotics. Tetrahedron 26, 2587 (1970).CrossRefGoogle Scholar
  17. 17.
    Morton, G. O., G. E. Van Lear, and W. Fulmor: The Structure of Mitiromycin. J. Amer. Chem. Soc. 92, 2588 (1970).CrossRefGoogle Scholar
  18. 18.
    Nomura, S., M. Yamamoto, I. Umeswara, A. Matsumae, and T. Hata: Studies on G-253 Substances, New Antibiotics from Streptomyces. I. J. Antibiotics 20, 55 (1967).Google Scholar
  19. 19.
    Taylor, W. G., and W. A. Remers: Structure and Stereochemistry of Some 1,2-Disubstituted Mitosenes from Solvolysis of Mitomycin C and Mitomycin A. J. Med. Chem. 18, 307 (1975).CrossRefGoogle Scholar
  20. 20.
    Cheng, L., and W. A. Remers: Comparative Stereochemistry in the Aziridine Ring Openings of N-Methylmitomycin A and 7-Methoxy-l,2-(N-methylaziridino)mitosene. J. Med. Chem. 20, 767 (1977).CrossRefGoogle Scholar
  21. 21.
    Kinoshita, S., K. Uzu, K. Nakano, and T. Takahashi: Mitomycin Derivatives. 2. Derivatives of Decarbamoylmitosane and Decarbamoylmitosene. J. Med. Chem. 14, 109 (1971).CrossRefGoogle Scholar
  22. 22.
    Kinoshita, S., K. Uzu, K. Nakano, and T. Takahashi: New Derivatives of Mitomycins: Decarbamoylmitomycin, Demethoxymitomycin, and N-Methylmitomycin B. Progress in Antimicrobial and Anticancer Chemotherapy, Vol. II (Proceedings of the 6th International Congress of Chemotherapy), p. 112–115. Baltimore: University Park Press. 1970.Google Scholar
  23. 23.
    Kishi, Y.: Harvard University, unpublished results.Google Scholar
  24. 24.
    Nakano, K.: Kyowa Hakko Kogyo, unpublished results.Google Scholar
  25. 25.
    Kinoshita, S., K. Uzu, K. Nakano, M. Shimizu, T. Takahashi, and M. Matsui: Mitomycin Derivatives. 1. Preparation of Mitosane and Mitosene Compounds and Their Biological Activities. J. Med. Chem. 14, 103 (1971).CrossRefGoogle Scholar
  26. 26.
    Patrick, J. B., R. P. Williams, W. E. Meyer, W. Fulmor, D. B. Cosulich, R. W. Broschard, and J. S. Webb: Aziridinomitosenes; A New Class of Antibiotics Related to the Mitomycins. J. Amer. Chem. Soc. 86, 1889 (1964).CrossRefGoogle Scholar
  27. 27.
    Moore, H. W.: Bioactivation as a Model for Drug Design: Bioreductive Alkylation. Science 197, 527 (1977).CrossRefGoogle Scholar
  28. 28.
    Iyer, V. N., and W. Szybalski: Mitomycins and Porfiromycin: Chemical Mechanism of Activation and Cross-Linking of DNA. Science 145, 55 (1964).CrossRefGoogle Scholar
  29. 29.
    Rao, G. M., J. W. Lown, and J. A. Plambeck: Electrochemical Studies of Antitumor Antibiotics. I. Cyclic Voltammetric Study of Mitomycin B. J. Electrochem. Soc. 124, 195 (1977).Google Scholar
  30. 30.
    Rao, G. M., A. Begleiter, J. W. Lown, and J. A. Plambeck: Electrochemical Studies of Antitumor Antibiotics. II. Polarographic and Cyclic Voltammetric Studies of Mitomycin. C. J. Electrochem. Soc. 124, 199 (1977).CrossRefGoogle Scholar
  31. 31.
    Tomasz, M., C. M. Mercado, J. Olson, and N. Chatterjie: The Mode of Interaction of Mitomycin C with Deoxyribonucleic Acid and Other Polynucleotides in Vitro. Biochemistry 13, 4878 (1974).CrossRefGoogle Scholar
  32. 32.
    Lown, J. W., A. Begleiter, D. Johnson, and A. R. Morgan: Studies Related to Antitumor Antibiotics. Part V. Reaction Mitomycin C with DNA Examined by Ethidium Fluorescence Assay. Canad. J. Biochem. 54, 110 (1976). — HSIUNG, H., J. W. LOWN, and D. JOHNSON: Effects of Alkylation by Dimethyl Sulfate, Nitrogen Mustard, and Mitomycin C on DNA Structure as Studied by the Ethidium Binding Assay. Canad. J. Biochem. 54, 1047 (1976).CrossRefGoogle Scholar
  33. 33.
    Moriguchi, I., and K. Komatsu: Adaptive Least Squares Classification Applied to Structure-Activity Correlation of Antitumor Mitomycin Derivatives. Chem. Pharm. Bull. 25, 2800 (1977).CrossRefGoogle Scholar
  34. 34.
    Weissbach, A., and A. Lisio: Alkylation of Nucleic Acids by Mitomycin C and Porfiromycin. Biochemistry 4, 196 (1965).CrossRefGoogle Scholar
  35. 35.
    Lipsett, M. N., and A. Weissbach: The Site of Alkylation of Nucleic Acids by Mitomycin C. Biochemistry 4, 206 (1965).CrossRefGoogle Scholar
  36. 36.
    Tomasz, M.: Novel Assay of 7-Alkylation of Guanine Residues in DNA. Application to Nitrogen Mustard, Triethylenemelamine and Mitomycin C. Biochim. Biophys. Acta 213, 288 (1970).Google Scholar
  37. 37.
    Crooke, S. T., and W. T. Bradner: Mitomycin C: A Review. Cancer Treat. Rev. 3, 121 (1976).CrossRefGoogle Scholar
  38. 38.
    Hornemann, U., and J. C. Cloyd: Studies on the Biosynthesis of the Mitomycin Antibiotics by Streptomyces Verticillatus. Chem. Commun. 1971, 301.Google Scholar
  39. 39.
    Hornemann, U., and M. J. Aikman: Mitomycin Biosynthesis by Streptomyces Verticillatus. Incorporation of the Amino-group of D-[15N] Glucosamine into the Aziridine Ring of Mitomycin B. Chem. Commun. 1973, 88.Google Scholar
  40. 40.
    Hornemann, U., J. P. Kehrer, C. S. Nunez, and R. L. Ranieri: D-Glucosamine and L-Citrulline, Precursors in Mitomycin Biosynthesis by Streptomyces Verticillatus. J. Amer. Chem. Soc. 96, 320 (1974).CrossRefGoogle Scholar
  41. 41.
    Kirsch, E. J., and J. D. Korshalla: Influence of Biological Methylation on the Biosynthesis of Mitomycin A. J. Bacteriol. 87, 247 (1964).Google Scholar
  42. 42.
    Bezanson, G. S., and L. C. Vining: Studies on the Biosynthesis of Mitomycin C. Canad. J. Biochem. 49, 911 (1971).CrossRefGoogle Scholar
  43. 43.
    Hornemann, U., J. P. Kehrer, and J. H. Eggert: Pyruvic Acid and D-Glucose as Precursors in Mitomycin Biosynthesis by Streptomyces Verticillatus. Chem. Commun. 1974, 1045.Google Scholar
  44. 44.
    Eggert, T., and K. Takahashi: Synthesis of Pyrrolo[l,2-a]indoles and Related Systems. Heterocycles 9, 293 (1978).CrossRefGoogle Scholar
  45. 45.
    Allen, Jr., G. R., J. F. Poletto, and M. J. Weiss: The Mitomycin Antibiotics. Synthetic Studies. V. Preparation of 7-Methoxymitosene. J. Organ. Chem. (USA) 30, 2897 (1965).Google Scholar
  46. 46.
    Leadbetter, G., D. L. Fost, N. M. Ekwuribe, and W. A. Remers: Mitomycin Antibiotics. Synthesis of 1-Substituted 7-Methoxymitosenes. J. Organ. Chem. (USA) 39, 3580 (1974).CrossRefGoogle Scholar
  47. 47.
    Taylor, W. G., G. Leadbetter, D. L. Fost, and W. A. Remers: Mitomycin Antibiotics. Synthesis and Activity of 1,2-Disubstituted Mitosenes. J. Med. Chem. 20, 138 (1977).CrossRefGoogle Scholar
  48. 48.
    Kametani, T., K. Takahashi, M. Ihara, and K. Fukumoto: Synthesis of 2,3-Dihydro- lH-pyrrolo[l,2-a]indoles by Intramolecular Nucleophilic Aromatic Substitution. J. Chem. Soc., Perkin I 1976, 389.Google Scholar
  49. 49.
    Yamada, Y., and M. Matsui: Study on the Synthesis of 7-Hydroxy-9-carbethoxy-2,3-dihydro-1 H-pyrrolo[1,2-a]indole. Agr. Biol. Chem. 35, 282 (1971).CrossRefGoogle Scholar
  50. 50.
    Takada, T., and M. Akiba: Synthesis of 1 H-Pyrrolo[1,2-a]indole Derivatives. III. Synthesis of 2,3-Dihydro-7-hydroxy-6,9-dimethyl-5,8-dioxo-l H-pyrrolo[1,2-a]indole. Chem. Pharm. Bull. (Japan) 20, 1785 (1972).CrossRefGoogle Scholar
  51. 51.
    Takada, T., Y. Kosugi, and M. Akiba: Reactions of Acylaminoquinone Tosyl- hydrazones 3. Simple Syntheses of 7-Substituted Pyrrolo[l,2-a]indole quinones and Related Compounds. Chem. Pharm. Bull. (Japan) 25, 543 (1977).CrossRefGoogle Scholar
  52. 52.
    Akiba, M., Y. Kosugi, and T. Takada: Reactions of Acylaminoquinone Tosyl- hydrazones. Synthesis of Pyrrolo[l,2-a]indoloquinones via Benzoxazoline by Thermolysis and Photolysis. Heterocycles 6, 1125 (1977).CrossRefGoogle Scholar
  53. 53.
    Rebek, Jr., J., and J. C. E. Gehret: A Synthetic Approach to the Mitosenes. Tetrahedron Letters 1977, 3027.Google Scholar
  54. 54.
    Anderson, W. K., and P. F. Corey: 1,3-Dipolar Cycloaddition Reactions with Isatin-N-acids. Synthesis of Dimethyl 9-Oxo-9H-pyrrole[l,2-a]indole-1,2-dicarboxylates. J. Organ. Chem. (USA) 42, 559 (1977).CrossRefGoogle Scholar
  55. 55.
    Germeraao, P., and H. W. Moore: Rearrangements of Azidoquinones. XII. Thermal Conversion of 2-Azido-3-vinyl-l,4-quinones to Indolequinones. J. Organ. Chem. (USA) 39, 774 (1974).CrossRefGoogle Scholar
  56. 56.
    Lown, J. W., and T. Itoh: Studies Related to Antitumor Antibiotics. Part III. Synthesis of l,2,3,4,5,6-Hexahydro-2,3-benzazocin-5-ones as Possible Intermediates in the Biosynthesis of Mitomycins. Canad. J. Chem. 53, 960 (1975).CrossRefGoogle Scholar
  57. 57.
    Itoh, T., T. Hata, and J. W. Lown: Synthetic Studies on Mitomycins. An Alternative Synthesis of 2,3-Dihydro-lH and 9H-Pyrrolo[l,2-a]indoles by Transannular Ring Closure. Heterocycles 4, 47 (1976).CrossRefGoogle Scholar
  58. 58.
    Kametani, T., K. Takahashi, M. Ihara, and K. Fukumoto: Interconversion Between Pyrrolo[l,2-a]indoles and 2,3-Benzazocin-5-ones — A Synthetic Approach to Mitomycins. Heterocycles 6, 1371 (1977).CrossRefGoogle Scholar
  59. 59.
    Remers, W. A., R. H. Roth, and M. J. Weiss: The Mitomycin Antibiotics. Synthetic Studies. VII. An Exploration of Pyrrolo[l,2-a]indole A-Ring Chemistry Directed toward the Introduction of the Aziridine Function. J. Organ. Chem. (USA) 30, 2910 (1965).CrossRefGoogle Scholar
  60. 60.
    Franck, R. W., and K. F. Bernady: A Study of the Acylation of a Tridentate Carbanion. J. Organ. Chem. (USA) 33, 3050 (1968).CrossRefGoogle Scholar
  61. 61.
    Hirata, T., Y. Yamada, and M. Matsui: Synthetic Studies on Mitomycins. Synthesis of Aziridino-Pyrrolo[l,2-a]indoles. Tetrahedron Letters 1969, 20.Google Scholar
  62. 62.
    Hirata, T., Y. Yamada, and M. Matsui: Synthetic Studies on Mitomycins. Part II. Synthesis of Aziridino-pyrrolo-[1,2-a] indoles. Tetrahedron Letters 1969, 4107.Google Scholar
  63. 63.
    Kametani, T., K. Takahashi, Y. Kigana, M. Ihara, and K. Fukumoto: Studies on the Synthesis of Heterocyclic Compounds. Part 676. Synthesis of 1-Substituted 7- Methoxymitosenes. J. Chem. Soc. Perkin I 1977, 28.Google Scholar
  64. 64.
    Auerbach, J., and R. W. Franck: A Synthesis of the Tetracyclic Mitomycin Nucleus. Chem. Commun. 1969, 991.Google Scholar
  65. 65.
    Franck, R. W., and J. Auerbach: The Singlet Oxygen Oxidation of N-Phenylpyrroles. Its Application to the Synthesis of a Model Mitomycin. J. Organ. Chem. (USA) 36, 31 (1971).CrossRefGoogle Scholar
  66. 66.
    Siuta, G. J., R. W. Franck, and R. J. Kempton: Studies Directed Toward a Mitomycin Synthesis. J. Organ. Chem. (USA) 39, 3739 (1974).CrossRefGoogle Scholar
  67. 67.
    Mandell, L., and E. C. Roberts: The Synthesis of 2-Methoxy-3-methyl-5-(2-carbethoxymethylpyrrolino)-p-benzoquinone, I. J. Hetero. Chem. 2, 479 (1965).CrossRefGoogle Scholar
  68. 68.
    Baldwin, J. E., J. Cutting, W. Dupont, L. Kruse, L. Silberman, and R. C. Thomas: 5-Endo-Trigonal Reactions: a Disfavoured Ring Closure. Chem. Commun. 1976, 736.Google Scholar
  69. 69.
    Danishefsky, S., and R. Doehner: A Route to Functionalized Mitosanes. Tetrahedron Letters 1976, 3031.Google Scholar
  70. 70.
    Akiba, M., Y. Kosugi, M. Okuyama, and T. Takada: A Convenient Photosynthesis of Aziridinopyrrolo[l,2-a]benz[f]indoloquinones and Heterocyclic Quinones as Model Compounds of Mitomycins by a One-Pot Reaction. J. Organ. Chem. (USA) 43, 181 (1978).CrossRefGoogle Scholar
  71. 71.
    Woodward, R. B., and R. Hoffmann: The Conservation of Orbital Symmetry, pp. 38–64. Weinheim: Verlag Chemie, GmbH. 1970.Google Scholar
  72. 72.
    Kametani, T., T. Ohsawa, M. Ihara, and K. Fukumoto: Studies on the Synthesis of Heterocyclic Compounds. Part 738. Photo-oxygenation of 9-Oxo-9H-pyrrolo[l,2-a]- indoles. J. Chem. Soc. Perkin I 1978, 460.Google Scholar
  73. 73.
    Franck, R. W., K. Miyano, and J. F. Blount: Approaches to the Mitomycins 4 4a-Secodeiminoquinones. Heterocycles 9, 807 (1978).CrossRefGoogle Scholar
  74. 74.
    Nakatsubo, F., A. J. Cocuzza, D. E. Keeley, and Y. Kishi: Synthetic Studies toward Mitomycins. 1. Total Synthesis of Deiminomitomycin A. J. Amer. Chem. Soc. 99, 4835 (1977).CrossRefGoogle Scholar
  75. 75.
    Nakatsubo, F., T. Fukuyama, A. J. Cocuzza, and Y. Kishi: Synthetic Studies toward Mitomycins. II. Total Synthesis of Porfiromycin. J. Amer. Chem. Soc. 99, 8115 (1977).CrossRefGoogle Scholar
  76. 76.
    Fukuyama, T., F. Nakatsubo, A. J. Cocuzza, and Y. Kishi: Synthetic Studies Toward Mitomycins. III. Total Syntheses of Mitomycins A and C. Tetrahedron Letters 1977, 4295.Google Scholar
  77. 77.
    Hornemann, U., Y.-K. Ho, J. K. Mackey, Jr., and S. C. Srivastava: Studies on the Mode of Action of the Mitomycin Antibiotics. Reversible Conversion of Mitomycin C into Sodium 7-Aminomitosane-9a-sulfonate. J. Amer. Chem. Soc. 98, 7069 (1976).CrossRefGoogle Scholar

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© Springer-Verlag/Wien 1979

Authors and Affiliations

  • R. W. Franck
    • 1
  1. 1.Department of ChemistryFordham UniversityBronxUSA

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