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    Synthesis and Evaluation of Radamide Analogues, A Chimera of Radicicol and Geldanamycin

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    Issue Date
    2009-07-03
    Author
    Hadden, M. Kyle
    Blagg, Brian S. J.
    Publisher
    American Chemical Society
    Type
    Article
    Article Version
    Scholarly/refereed, author accepted manuscript
    Rights
    This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Organic Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jo900278g.
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    Abstract
    Previously, we reported the Hsp90 inhibitory activity of radamide, an open chain amide chimera of geldanamycin and radicicol. Attempts to further expand upon structure–activity relationships for this class of Hsp90 inhibitors led to the preparation of a series of radamide analogues focused on differing tether lengths and quinone mimics. In addition, the cup-shaped conformation adopted by the two natural products when bound to the Hsp90 N-terminal ATP binding pocket suggests that conformationally biased compounds may demonstrate improved binding and inhibition. The preparation and evaluation of radamide analogues with cis/trans α,β-unsaturated amides yielded compounds that exhibit improved antiproliferative activity. In addition, several analogues demonstrated the ability to induce degradation of Hsp90-dependent oncogenic signaling proteins in vitro, a hallmark of Hsp90 N-terminal inhibition.
    URI
    http://hdl.handle.net/1808/23680
    DOI
    https://doi.org/10.1021/jo900278g
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    • Medicinal Chemistry Scholarly Works [242]
    Citation
    Hadden, M. K., & Blagg, B. S. J. (2009). Synthesis and Evaluation of Radamide Analogues, A Chimera of Radicicol and Geldanamycin. The Journal of Organic Chemistry, 74(13), 4697–4704. http://doi.org/10.1021/jo900278g

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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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