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    Exquisite Selectivity For Human Toll-like Receptor 8 in Substituted Furo[2,3-c]quinolines

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    Issue Date
    2013-09-12
    Author
    Kokatla, Hari Prasad
    Sil, Diptesh
    Malladi, Subbalakshmi S.
    Balakrishna, Rajalakshmi
    Hermanson, Alec R.
    Fox, Lauren M.
    Wang, Xinkun
    Dixit, Anshuman
    David, Sunil A.
    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/jm400694d.
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    Abstract
    Toll-like receptor (TLR)-8 agonists activate adaptive immune responses by inducing robust production of T helper 1-polarizing cytokines, suggesting that TLR8-active compounds may be promising candidate adjuvants. We synthesized and evaluated hitherto unexplored furo[2,3-c]quinolines and its regioisomeric furo[3,2-c]quinolines, derived via a tandem, one-pot Sonogashira coupling and intramolecular 5 endo-dig cyclization strategy, in a panel of primary screens. We observed a pure TLR8 agonistic activity profile in select furo[2,3-c]quinolines, with maximal potency conferred by a C2-butyl group (EC50: 1.6 µM); shorter, longer, or substituted homologues, as well as compounds bearing C1 substitutions were inactive, which was rationalized by docking studies using the recently-described crystal structure of human TLR8. The best-in-class compound displayed prominent proinflammatory cytokine induction (including interleukin-12 and interleukin-18), but was bereft of interferon-α inducing properties, confirming its high selectivity for human TLR8.
    URI
    http://hdl.handle.net/1808/23592
    DOI
    https://doi.org/10.1021/jm400694d
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    • Medicinal Chemistry Scholarly Works [243]
    Citation
    Kokatla, H. P., Sil, D., Malladi, S. S., Balakrishna, R., Hermanson, A. R., Fox, L. M., … David, S. A. (2013). Exquisite Selectivity For Human Toll-like Receptor 8 in Substituted Furo[2,3-c]quinolines. Journal of Medicinal Chemistry, 56(17), 6871–6885. http://doi.org/10.1021/jm400694d

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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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