Recent Studies on Bleomycin

  • H. Umezawa

Abstract

The structures of bleomycins, including their stereochemistry as shown in Figure 1, were conclusively determined by a study in the author’s institute in 1978 (Takita, Muraoka, Nakatani, Fujii, Umezawa, Naganawa & Umezawa, 1978b). The N-terminal amino acid contained in the bleomycin molecule was called pyrimidoblamic acid. Demethylpyrimidoblamylhistidylalanine which was thought to be a biosynthetic intermediate was isolated from a culture filtrate of a bleomycin-producing strain and its copper complex was crystallized. The structure of bleomycin shown in Figure 1 has been supported by crystal X-ray analysis and also by the chemical synthesis of pyrimidoblamic acid. Moreover, this structure has been confirmed by 15N-n.m.r. of bleomycin A2 (Naganawa, Takita, Umezawa & Hull, 1979) and also by mass spectroscopic analysis of bleomycins Bľ which gave the exact molecular weight of bleomycin (Macfarlane, Fujii, Takita & Umezawa, 1980). The main structural group common to all bleomycins is called bleomycinic acid (Figure 1). Bleomycinic acid consists of a peptide moiety, pyrimidoblamyl-β — hydroxy-histidyl- (4-amino-3-hydroxy-2-methyl) pentanoyl-thereonyl-2′- (2-aminoethyl)-2,4′-bithiazole-4-carboxylic acid, and a disaccharide part, 2-o-(3-o-carbamoyl-d-mannopyranosyl) -l-gulopyranoside. Bleomycin consists of bleomycinic acid and a terminal amine. As shown in Figure 1, various bleomycins which are different from one another in the terminal amine are produced by a bleomycin-producing strain. The present bleomycin used clinically consists mainly of bleomycins A2 and B2.

Keywords

Fermentation Hull Alkaloid Hydrolase Bleomycin 

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References

  1. Edsmyr, F. (1976). Combined treatment with bleomycin in penile carcinomas. In GANN Monograph on Cancer Research, No. 19, pp. 231–234. University of Tokyo Press.Google Scholar
  2. Ekimoto. H., Kuramochi, H., Takahashi, K., Matsuda, A. & Umezawa, H. (1980). Kinetics of the reaction of bleomycin-Fe(II)-O2 complex with DNA. J. Antibiot., 33, 426–434.CrossRefPubMedGoogle Scholar
  3. Fukuoka, T., Muraoka, Y., Fujii, A., Naganawa, H., Takita, T. & Umezawa, H. (1980). Chemistry of bleomycin. XXV. Reductive methylation of bleomycin, a chemical proof for the presence of the free secondary amine in bleomycin. J. Antibiot. 33, 114–117.CrossRefPubMedGoogle Scholar
  4. Kasai, H., Naganawa, H., Takita, T. & Umezawa, H. (1978). Chemistry of bleomycin. XXII. Interaction of bleomycin with nucleic acids, preferential binding to guanine base and electrostatic effect of the terminal amine. J. Antibiot., 31, 1316–1320.CrossRefPubMedGoogle Scholar
  5. Macfarlane, R. D., Fujii, A., Takita, T. & Umezawa, H. (1980). 252Cf-plasma desorption mass spectrometry of bleomycin. Proceedings of the 15th Organic Mass Spectrometry Symposium, pp. 175–178. Nagoya, Japan.Google Scholar
  6. Matsuda, A., Yoskhioka, O., Takahashi, K., Yamashita, T., Ebihara, K., Ekimoto, A., Abe, F., Hashimoto, Y. & Umezawa, H. (1978a). Preclinical studies on bleomycin-PEP. In Bleomycin: Current Status and New Development, pp. 311–331. London & New York: Academic Press.Google Scholar
  7. Matsuda, A., Yoskhioka, O., Yamashita, T., Ebihara, K., Umezawa, H., Miura, T., Katayama, K., Yokoyama, M. & Nagai, S. (1978b). Fundamental and clinical studies on new bleomycins. In Bleomycin: Current Status and New Development, pp. 191–211. London & New York: Academic Press.Google Scholar
  8. Müller, W. E. G. & Zahn, R. K. (1976). Bleomycin: mode of action on DNA. In GANN Monograph of Cancer Research, No. 19, pp. 51–62. University of Tokyo Press.Google Scholar
  9. Naganawa, H., Takita, T., Umezawa, H. & Hull, W. E. (1979). Chemistry of bleomycin. XXIII. Natural abundance 15N-NMR spectroscopic evidence for the structure of bleomycin. J. Antibiot., 32, 539–541.CrossRefPubMedGoogle Scholar
  10. Nouel, J. P. (1976). Radioactive metal bleomycin complex for the diagnosis of cancer. In GANN Monograph on Cancer Research No. 19, pp. 301–306. University of Tokyo Press.Google Scholar
  11. Oppenheimer, N. J., Rodriguez, L. O. & Hecht, S. M. (1979). Structural studies of ‘active complex’ of bleomycin: Assignment of ligands to the ferrous ion in a ferrous-bleomycin-carbon monoxide complex. Proc. Nat. Acad. Sci. USA, 76, 5616–5620.PubMedCentralCrossRefPubMedGoogle Scholar
  12. Takahashi, K., Yoshioka, O., Matsuda, A. & Umezawa, H. (1977). Intracellular reduction of the cupric ion of bleomycin copper complex and transfer or the cuprous ion to a cellular protein. J. Antiobiot., 30, 861–869.CrossRefGoogle Scholar
  13. Takita, T., Muraoka, Y., Nakatani, T., Fujii, A., Iitaka, Y. & Umezawa, H. (1978a). Chemistry of bleomycin. XXI. Metal-complex of bleomycin and its implication for the mechanism of bleomycin action. J. Antibiot., 31, 1073–1077.CrossRefPubMedGoogle Scholar
  14. Takita, T., Muraoka, Y., Nakatani, T., Fujii, A., Umezawa, Y., Naganawa, H. & Umezawa, H. (1978b). Chemistry of bleomycin. XIX. Revised structures of bleomycin and phleomycin. J. Antibiot., 31, 801–804.CrossRefPubMedGoogle Scholar
  15. Umezawa, H. (1976). Bleomycin: Discovery, chemistry and action. In GANN Monograph on Cancer Research No. 19, pp. 3–36. University of Tokyo Press.Google Scholar
  16. Umezawa, H. (1979). Recent advances in microbial secondary metabolites: Inhibitors of hydrolytic enzymes. In Kinin II: Systemic and Cellular Function, pp. 319–340. Plenum Publishing Co.Google Scholar
  17. Umezawa, H., Hori, S., Sawa, T., Yoshioka, T. & Takeuchi, T. (1974). A bleomycin-inactivating enzyme in mouse liver. J. Antibiot., 27, 419–424.CrossRefPubMedGoogle Scholar
  18. Umezawa, H., Ishizuka, M, Aoyagi, T. & Takeuchi, T. (1976). Enhancement of delayed-type hypersensitivity by bestatin an inhibitor of aminopeptidase B and leucine aminopeptidase. J. Antibiot., 29, 857–859.CrossRefPubMedGoogle Scholar
  19. Umezawa, H. & Takita, T. (1980). The bleomycins: Antitumor copper-binding antibiotics. In Structure and Bonding Vol. 40, pp. 73–99. Springer-Verlag.Google Scholar
  20. Yagoda, A. & Krakoff, I. H. (1976). Observations on the use of bleomycin in the treatment of malignant lymphoma in U.S.A. In GANN Monograph on Cancer Research No. 19, pp. 255–269. University of Tokyo Press.Google Scholar

Copyright information

© The contributors 1980

Authors and Affiliations

  • H. Umezawa
    • 1
  1. 1.Institute of Microbial ChemistryShinagawa-ku, TokyoJapan

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