Open saccharin-based secondary sulfonamides as potent and selective inhibitors of cancer-related carbonic anhydrase IX and XII isoforms

Melissa D'Ascenzio, Paolo Guglielmi (Lead / Corresponding author), Simone Carradori, Daniela Secci, Rosalba Florio, Adriano Mollica, Mariangela Ceruso, Atilla Akdemir, Anatoly P. Sobolev, Claudiu T. Supuran

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    32 Citations (Scopus)
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    Abstract

    A large number of novel secondary sulfonamides based on the open saccharin scaffold were synthesized and evaluated as selective inhibitors of four different isoforms of human carbonic anhydrase (hCA I, II, IX and XII, EC 4.2.1.1). They were obtained by reductive ring opening of the newly synthesized N-alkylated saccharin derivatives and were shown to be inactive against the two cytosolic off-target hCA I and II (Kis > 10 µM). Interestingly, these compounds inhibited hCA IX in the low nanomolar range with Kis ranging between 20 and 298 nM and were extremely potent inhibitors of hCA XII isoenzyme (Kis ranging between 4.3 and 432 nM). Since hCA IX and XII are the cancer-related isoforms recently validated as drug targets, these results represent an important goal in the development of new anticancer candidates. Finally, a computational approach has been performed to better correlate the biological data to the binding mode of these inhibitors.

    Original languageEnglish
    Pages (from-to)51-59
    Number of pages9
    JournalJournal of Enzyme Inhibition and Medicinal Chemistry
    Volume32
    Issue number1
    Early online date26 Oct 2016
    DOIs
    Publication statusPublished - 2017

    Keywords

    • Cancer-related isoforms
    • Saccharin
    • Secondary sulphonamides
    • Selective carbonic anhydrase inhibitors

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