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    Total Synthesis and Evaluation of c26-Hydroxyepothilone D Derivatives for Photoaffinity Labeling of β-Tubulin

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    Issue Date
    2010-01-01
    Author
    Reiff, Emily A.
    Nair, Sajiv K.
    Henri, John T.
    Greiner, Jack F.
    Reddy, Bollu S.
    Chakrasali, Ramappa
    David, Sunil A.
    Chiu, Ting-Lan
    Amin, Elizabeth A.
    Himes, Richard H.
    Velde, G. Vander
    Georg, Gunda I.
    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/jo901752v.
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    Abstract
    Three photaffinity labeled derivatives of epothilone D were prepared by total synthesis, using efficient novel asymmetric synthesis methods for the preparation of two important synthetic building blocks. The key step for the asymmetric synthesis of (S,E)-3-(tert-butyldimethylsilyloxy)-4-methyl-5-(2-methylthiazol-4-yl)pent-4-enal involved a ketone reduction with (R)-Me-CBS-oxazaborolidine. For the synthesis of (5S)-5,7-di-[(tert-butyldimethylsilyl)oxy]-4,4-dimethylheptan-3-one an asymmetric Noyori reduction of a β-ketoester was employed. The C26 hydroxyepothilone D derivative was constructed following a well-established total synthesis strategy and the photoaffinity labels were attached to the C26 hydroxyl group. The photoaffinity analogues were tested in a tubulin assembly assay and for cytotoxicity against MCF-7 and HCT-116 cancer cell lines. The 3- and 4-azidobenzoic acid analogues were found to be as active as epothilone B in a tubulin assembly assay, but demonstrated significantly reduced cellular cytotoxicity compared to epothilone B. The benzophenone analogue was inactive in both assays. Docking and scoring studies were conducted that suggested that the azide analogues can bind to the epothilone binding site, but that the benzophenone analogue undergoes a sterically driven ligand rearrangement that interrupts all hydrogen bonding and therefore protein binding. Photoaffinity labeling studies with the 3-azidobenzoic acid derivative did not identify any covalently labeled peptide fragments, suggesting that the phenylazido side chain was predominantly solvent-exposed in the bound conformation.
    URI
    http://hdl.handle.net/1808/23725
    DOI
    https://doi.org/10.1021/jo901752v
    Collections
    • Medicinal Chemistry Scholarly Works [242]
    Citation
    Reiff, E. A., Nair, S. K., Henri, J. T., Greiner, J. F., Reddy, B. S., Chakrasali, R., … Georg, G. I. (2010). Total Synthesis and Evaluation of C26-Hydroxyepothilone D Derivatives for Photoaffinity Labeling of β-Tubulin. The Journal of Organic Chemistry, 75(1), 86–94. http://doi.org/10.1021/jo901752v

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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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