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    Optimization of Potent Hepatitis C Virus NS3 Helicase Inhibitors Isolated from the Yellow Dyes Thioflavine S Primuline

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    Frankowski_2012.pdf (839.2Kb)
    Issue Date
    2012-04-12
    Author
    Li, Kelin
    Frankowski, Kevin J.
    Belon, Craig A.
    Neuenswander, Benjamin
    Ndjomou, Jean
    Hanson, Alicia M.
    Shanahan, Matthew A.
    Schoenen, Frank J.
    Blagg, Brian S. J.
    Aubé, Jeffrey
    Frick, David N.
    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 Medicinal 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/jm300021v.
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    Abstract
    A screen for hepatitis C virus (HCV) NS3 helicase inhibitors revealed that the commercial dye thioflavine S was the most potent inhibitor of NS3-catalyzed DNA and RNA unwinding in the 827-compound National Cancer Institute Mechanistic Set. Thioflavine S and the related dye primuline were separated here into their pure components, all of which were oligomers of substituted benzothiazoles. The most potent compound (P4), a benzothiazole tetramer, inhibited unwinding >50% at 2±1 μM, inhibited the subgenomic HCV replicon at 10 μM, and was not toxic at 100 μM. Because P4 also interacted with DNA, more specific analogs were synthesized from the abundant dimeric component of primuline. Some of the 29 analogs prepared retained ability to inhibit HCV helicase but did not appear to interact with DNA. The most potent of these specific helicase inhibitors (compound 17) was active against the replicon and inhibited the helicase more than 50% at 2.6±1 μM.
    URI
    http://hdl.handle.net/1808/23594
    DOI
    https://doi.org/10.1021/jm300021v
    Collections
    • Medicinal Chemistry Scholarly Works [242]
    Citation
    Li, K., Frankowski, K. J., Belon, C. A., Neuenswander, B., Ndjomou, J., Hanson, A. M., … Frick, D. N. (2012). Optimization of Potent Hepatitis C Virus NS3 Helicase Inhibitors Isolated from the Yellow Dyes Thioflavine S and Primuline. Journal of Medicinal Chemistry, 55(7), 3319–3330. http://doi.org/10.1021/jm300021v

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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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