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Synthetic Study on Man-Made Bleomycins Based on the Anticancer Mechanism of Natural Bleomycins

  • Masaji Ohno
  • Masami Otsuka

Abstract

Antitumor activity of bleomycins (BLMs) is attributed to oxygen activation and DNA cleavage by formation of iron chelate of the unusual glycopeptide, erythro-β-Hydroxy-l-histidine, a novel amino acid constituent of BLM and a pivotal amino acid for the biological activity, has been prepared based on the stereocontrolled aldol strategy using chiral 1,3-oxazolidin-2-one auxiliary. In order to study the biochemical functions of BLM, model compounds have been designed, synthesized, and characterized. In particular, model ligands with a 4-methoxypyridine (PYML-6) and 4- dimethylaminopyridine (PYML-8) showed oxygen activation up to 97% and 125% of that of BLM, respectively. cis-β-Methylstyrene was oxidized either with the Fe(III)-H2O2 or with Fe(II)-O2 complex systems of BLM and PYML-6 to afford the corresponding optically active epoxide, showing that the environment around the iron center is chiral enough to cause asymmetric epoxidation. PYML-6 was coupled with distamycin to afford a man-made BLM, PYML(6)- (4R-APA)-distamycin, which exhibited dramatically altered sequence-specific cleavage of DNA, indicating clearly that recognition of AT bases by the distamycin moiety is crucial.

Keywords

Metal Binding Site Amino Acid Constituent Synthetic Study Asymmetric Epoxidation Pyrimidine Moiety 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer-Verlag Berlin Heidelberg 1990

Authors and Affiliations

  • Masaji Ohno
    • 1
  • Masami Otsuka
    • 1
  1. 1.Faculty of Pharmaceutical SciencesUniversity of TokyoHongo, Bunkyo-ku, Tokyo 113Japan

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