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Oxime-Based Click Chemistry in the Development of 3-Isoxazolecarboxylic Acid Containing Inhibitors of Yersinia pestis Protein Tyrosine Phosphatase, YopH

  1. Author:
    Bahta, M.
    Burke, T. R.

  2. Author Address

    [Bahta, M; Burke, TR] NCI, Biol Chem Lab, Mol Discovery Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA.;Bahta, M (reprint author), NCI, Biol Chem Lab, Mol Discovery Program, Ctr Canc Res,NIH, POB,Bldg 376,Boyles St, Frederick, MD 21702 USA;tburke@helix.nih.gov
    1. Year: 2011
    2. Date: Aug
  2. Journal: Chemmedchem
    1. 6
    2. 8
    3. Pages: 1363-1370
  4. Type of Article: Article
  5. ISSN: 1860-7179
  1. Abstract:

    The pathogenicity of Yersinia pestis relies on several effector proteins including YopH, a protein tyrosine phosphatase (PTP). We previously screened a library of analogues based on the ubiquitous PTP substrate para-nitrophenylphosphate (pNPP) and found that incorporation of a 3-phenyl substituent to give 6-nitro-[1,1'-biphenyl]-3-yldihydrogen phosphate (1) enhanced affinity. Herein we report the conversion of 1 from a substrate into an inhibitor by replacing the hydrolysable phosphoryl group with a 3-isoxazolecarboxylic acid moiety and by introduction of an aminooxy group and subsequent diversification using oxime-based click chemistry. This approach led to the identification of non-promiscuous bidentate YopH inhibitors with affinity in the low micromolar range.

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External Sources

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  2. DOI: 10.1002/cmdc.201100200
  3. View record in Web of Science®
  4. WOS: 000294112900006

Library Notes

  1. Fiscal Year: FY2010-2011
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