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Carbonic Anhydrase Inhibitors: Glycosylsulfanilamides Act as Subnanomolar Inhibitors of the Human Secreted Isoform VI

Authors

  • Jean-Yves Winum,

    Corresponding author
    1. Institut des Biomolécules Max Mousseron (IBMM) UMR 5247 CNRS-UM1-UM2 Bâtiment de Recherche Max Mousseron, Ecole Nationale Supérieure de Chimie de Montpellier, 8 rue de l’Ecole Normale, 34296 Montpellier Cedex, France
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  • Jean-Louis Montero,

    1. Institut des Biomolécules Max Mousseron (IBMM) UMR 5247 CNRS-UM1-UM2 Bâtiment de Recherche Max Mousseron, Ecole Nationale Supérieure de Chimie de Montpellier, 8 rue de l’Ecole Normale, 34296 Montpellier Cedex, France
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  • Daniela Vullo,

    1. Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino Florence, Italy
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  • Claudiu T. Supuran

    Corresponding author
    1. Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino Florence, Italy
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*Corresponding authors: Jean-Yves Winum, jean-yves.winum@univ-montp2.fr and Claudiu T. Supuran, claudiu.supuran@unifi.it

Abstract

A series of sulfonamides incorporating sugar moieties and the sulfanilamide scaffold have been investigated for their interaction with the secretory isoform of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), CA VI. This isoform is secreted in saliva, tears, and milk of mammals – where it plays important physiological roles – even if little is understood at this moment regarding its inhibition, due to the lack of potent and/or selective inhibitors. Here we report a series of low nanomolar and subnanomolar CA VI inhibitors, belonging to the glycosylamine–sulfanilamide class. The glucose, ribose, arabinose, xylose, and fucose derivatives showed excellent CA VI inhibitory activity, with Kis in the range of 0.56–5.1 nm, whereas the least active derivatives, incorporating gallactose, mannose, and rhamnose scaffolds showed inhibition constants in the range of 10.1–34.1 nm. Many of these sulfonamides were also selective inhibitors for their interaction with CA VI over the physiologically dominant and ubiquitous isoform CA II, with selectivity ratios of 4.11–35.93 for inhibiting the secreted over the cytosolic isozyme. Because of their high water solubility and high affinity for CA VI over CA II, these compounds are useful tools for better understanding the secreted CA isoform CA VI.

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