Halogenated analogs of 1′-acetoxychavicol acetate, Rev-export inhibitor from Alpinia galanga, designed from mechanism of action

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Abstract

In the course of search for the robust analogs of 1′-acetoxychavicol acetate (ACA, 1), the Rev-export inhibitor from the medicinal plant Alpinia galanga, we clarified formation of the quinone methide intermediate ii to be essential for exerting the inhibitory activity of 1. Based on this mechanism of action, the rational design from the MO calculation of the conclusive activation energy to ii resulted in the four halogenated analogs with more potent activity than ACA (1). In particular, the difluoroanalog 20d exhibited approximately four-fold potent activity as compared with 1.

Graphical abstract

Rational design based on the mechanism of action disclosed the four halogenated analogs (20a20d) as the more potent Rev-export inhibitors than 1′-acetoxychavicol acetate (1).

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Acknowledgments

We wish to thank Professor Minoru Yoshida in RIKEN Advanced Science Institute for giving the fission yeast S. pombe. This work was supported in part by Grants-in-Aid for Scientific Research (Grant No. 19590100) from the Ministry of Education, Science, Culture and Sports. The authors are grateful to the Shorai Foundation for Science and Technology for financial support.

References and notes (20)

  • J. Kjems et al.

    Adv. Pharmacol.

    (2000)
  • S. Tamura et al.

    Bioorg. Med. Chem. Lett.

    (2009)
  • N. Murakami et al.

    Bioorg. Med. Chem. Lett.

    (2004)
  • N. Kudo et al.

    Exp. Cell Res.

    (1998)
  • N. Murakami et al.

    Bioorg. Med. Chem. Lett.

    (2002)
  • O. García et al.

    Tetrahedron Lett.

    (2003)
  • H. Matsuda et al.

    Bioorg. Med. Chem. Lett.

    (2005)
  • T.J. Daly et al.

    Nature (London)

    (1989)
  • N. Murakami et al.

    J. Med. Chem.

    (2003)
There are more references available in the full text version of this article.

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