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  • Fragment-based drug discovery of carbonic anhydrase II inhibitors by dynamic combinatorial chemistry utilizing alkene cross metathesis

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    Author(s)
    Poulsen, SA
    Bornaghi, LF
    Griffith University Author(s)
    Poulsen, Sally-Ann
    Year published
    2006
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    Abstract
    A fragment-based drug discovery approach to the synthesis and identification of small molecule inhibitors of bovine carbonic anhydrase II (bCA II) is described. The classical bCA II recognition fragment is an aromatic sulfonamide (ArSO2NH2) moiety. This fragment was incorporated into a scaffold building block, which was subsequently derivatized by dynamic combinatorial chemistry utilizing alkene cross metathesis as the reversible reaction. Screening against bCA II was then carried out and the results allowed determination of the relative bCA II binding affinities of the cross metathesis products that contained the ArSO2NH2 ...
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    A fragment-based drug discovery approach to the synthesis and identification of small molecule inhibitors of bovine carbonic anhydrase II (bCA II) is described. The classical bCA II recognition fragment is an aromatic sulfonamide (ArSO2NH2) moiety. This fragment was incorporated into a scaffold building block, which was subsequently derivatized by dynamic combinatorial chemistry utilizing alkene cross metathesis as the reversible reaction. Screening against bCA II was then carried out and the results allowed determination of the relative bCA II binding affinities of the cross metathesis products that contained the ArSO2NH2 fragment. A bCA II competitive binding assay validated these results with a representative number of pure compounds. The results for screening, without prior isolation of the active constituent, were in full agreement with those obtained for equilibrium dissociation constants (Ki's) of pure compounds. Some of these compounds exhibited Ki's in the low nanomolar range. Heterogeneous catalysis was shown to be very effective in this drug discovery application of dynamic combinatorial chemistry.
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    Journal Title
    Bioorganic & Medicinal Chemistry
    Volume
    14
    Issue
    10
    Publisher URI
    http://www.elsevier.com/wps/find/journaldescription.cws_home/129/description#description
    DOI
    https://doi.org/10.1016/j.bmc.2005.12.054
    Copyright Statement
    © 2006 Elsevier. This is the author-manuscript version of this paper. Reproduced in accordance with the copyright policy of the publisher. Please refer to the journal's website for access to the definitive, published version.
    Subject
    Medicinal and biomolecular chemistry
    Organic chemistry
    Pharmacology and pharmaceutical sciences
    Publication URI
    http://hdl.handle.net/10072/14469
    Collection
    • Journal articles

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