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Benzenesulfonamides bearing pyrrolidinone moiety as inhibitors of carbonic anhydrase IX: synthesis and binding studies

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Abstract

A series of novel compounds bearing substituted pyrrolidinone moieties at the para-position of benzenesulfonamide was synthesized as inhibitors of carbonic anhydrase (CA) isoform IX, known to be overexpressed in numerous human cancers. The inhibitors were tested towards all twelve catalytically active human CA isozymes to determine the affinity and selectivity towards CA IX over other isoforms. Compound affinity was determined by the fluorescence-based thermal shift assay and verified by isothermal titration calorimetry. Several compounds exhibited nanomolar binding affinity against CA IX while significantly weaker binding to the cytosolic off-target CA I was observed. The most effective CA IX binders reached the K d of about 50 nM. This series of compounds can be used for further development of inhibitors with significant binding affinity and selectivity towards anticancer CA IX isozyme.

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Acknowledgments

This research was funded by the grant (No. TAP LLT-1/2016) from the Research Council of Lithuania.

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Authors and Affiliations

  1. Department of Organic Chemistry, Kaunas University of Technology, Kaunas, LT-50254, Lithuania

    Kęstutis Rutkauskas, Ingrida Tumosienė & Vytautas Mickevičius

  2. Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio 7, Vilnius, LT-10257, Lithuania

    Asta Zubrienė & Daumantas Matulis

  3. Department of Physical and Inorganic Chemistry, Kaunas University of Technology, Kaunas, LT-50254, Lithuania

    Kristina Kantminienė

Authors
  1. Kęstutis Rutkauskas
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  2. Asta Zubrienė
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  3. Ingrida Tumosienė
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  4. Kristina Kantminienė
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  5. Vytautas Mickevičius
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  6. Daumantas Matulis
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Corresponding author

Correspondence to Asta Zubrienė.

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Rutkauskas, K., Zubrienė, A., Tumosienė, I. et al. Benzenesulfonamides bearing pyrrolidinone moiety as inhibitors of carbonic anhydrase IX: synthesis and binding studies. Med Chem Res 26, 235–246 (2017). https://doi.org/10.1007/s00044-016-1741-5

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  • DOI: https://doi.org/10.1007/s00044-016-1741-5

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