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Total Synthesis of Syringolin A and Improvement of Its Biological Activity

Authors

  • Takuya Chiba,

    1. Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812 (Japan)
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  • Hidetaka Hosono,

    1. Graduate School of Medicine, Department of Cancer Preventive Medicine, Hokkaido University, Kita-12, Nishi-7, Kita-ku, Sapporo, 060-0812 (Japan)
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  • Koji Nakagawa,

    1. Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812 (Japan)
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  • Masahiro Asaka,

    1. Graduate School of Medicine, Department of Cancer Preventive Medicine, Hokkaido University, Kita-12, Nishi-7, Kita-ku, Sapporo, 060-0812 (Japan)
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  • Hiroshi Takeda,

    1. Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812 (Japan)
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  • Akira Matsuda,

    1. Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812 (Japan)
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  • Satoshi Ichikawa

    Corresponding author
    1. Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812 (Japan)
    2. Center for Research and Education on Drug Discovery, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812 (Japan)
    • Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812 (Japan)===

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Abstract

The development process for syringolin A analogues having improved proteasome inhibitory and antitumor activity is described. The strategy was to first establish a convergent synthesis of syringolin A using a rare intramolecular Ugi three-component reaction in the last stage of the synthesis, so as to gain access toa set of structure-based analogues. The inhibitory activity of chymotrypsin-like activity of 20S proteasome was largely improved by targeting the S3 subsite of the β5 subunit. Cytotoxic activity was also improved by installing the membrane-permeable substituent. These biological properties are comparable to those of bortezomib, a clinically used first-line proteasome inhibitor.

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