Synthesis and evaluation of quinazolin-4-ones as hypoxia-inducible factor-1α inhibitors

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Abstract

Quinazolin-4-one 1 was identified as an inhibitor of the HIF-1α transcriptional factor from a high-throughput screen. HIF-1α up-regulation is common in many cancer cells. In this Letter, we describe an efficient one-pot sequential reaction for the synthesis of quinazolin-4-one 1 analogues. The structure–activity relationship (SAR) study led to the 5-fold more potent analogue, 16.

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Acknowledgments

We thank Paul Shinn and Danielle Van Leer for compound management, William Leister and Jeremy Smith for analytical chemistry. This research was supported by the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research, National Institutes of Health.

References and notes (10)

  • N. Yewalkar et al.

    Bioorg. Med. Chem. Lett.

    (2010)
    S.-Y. Park et al.

    J. Pineal Res.

    (2010)
    K. Shimizu et al.

    Bioorg. Med. Chem. Lett.

    (2010)
    T. Narita et al.

    Clin. Cancer Res.

    (2009)
    A.C. Kasper et al.

    Bioorg. Med. Chem. Lett.

    (2009)
    M.-S. Won et al.

    Biochem. Biophys. Res. Commun.

    (2009)
    M. Uno et al.

    Bioorg. Med. Chem. Lett.

    (2009)
    J.A. Diaz-Gonzalez et al.

    Cancer Biol. Ther.

    (2005)
    H. Harada et al.

    Curr. Signal Transduction Ther.

    (2010)
    S.R. Mooring et al.

    Sci. China:Chem.

    (2011)
    Y. Li et al.

    Curr. Cancer Drug Tar.

    (2010)
    G. Semenza

    Drug Discovery Today

    (2007)
    R.J. DeBerardinis et al.

    Cell Metab.

    (2008)
    X.-H. Wang et al.

    Biochem. Pharmacol.

    (2009)
    P. Garcia-Maceira et al.

    Oncogene

    (2009)
    S.H. Li et al.

    Mol. Cancer Ther.

    (2008)
    L.M. Greenberger et al.

    Mol. Cancer Ther.

    (2008)
    H.S. Ban et al.

    Expert Opin. Ther. Patents

    (2011)
  • M. Xia et al.

    Mol. Cancer

    (2009)
  • Becklin, R. R.; Chepanoske, C. L.; Pelter, J. M.; Qi, L.; Robbins, P. B.; Sahasrabudhe, S. R.; Selliah, R.; Simmons,...
  • J.F. Liu et al.

    Tetrahedron Lett.

    (2005)
There are more references available in the full text version of this article.

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