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

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Recent Progress in the Chemical Synthesis of Antibiotics

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.

Synthetic Studies on Antitumor Antibiotic, Bleomycin. XXIX. For Part XXVIII, see Ref. [61]

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Authors and Affiliations

  1. Faculty of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113, Japan

    Masaji Ohno & Masami Otsuka

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  1. Masaji Ohno
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  2. Masami Otsuka
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  1. Institut de Chimie des Substances Naturelles du C.N.R.S., Avenue de la Terrasse, F-91198, Gif-sur-Yvette Cedex, France

    G. Lukacs (Directeur de Recherche C.N.R.S.) (Directeur de Recherche C.N.R.S.)

  2. University of Tokyo, 7-3-1 Hongo, Bunkyo-ku Tokyo 113, Japan

    M. Ohno

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© 1990 Springer-Verlag Berlin Heidelberg

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Ohno, M., Otsuka, M. (1990). Synthetic Study on Man-Made Bleomycins Based on the Anticancer Mechanism of Natural Bleomycins. In: Lukacs, G., Ohno, M. (eds) Recent Progress in the Chemical Synthesis of Antibiotics. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-75617-7_11

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  • DOI: https://doi.org/10.1007/978-3-642-75617-7_11

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