Bioorganic & Medicinal Chemistry 2013-03-15

Superacid synthesis of halogen containing N-substituted-4-aminobenzene sulfonamides: new selective tumor-associated carbonic anhydrase inhibitors.

Guillaume Compain, Agnès Martin-Mingot, Alfonso Maresca, Sebastien Thibaudeau, Claudiu T Supuran

Index: Bioorg. Med. Chem. 21(6) , 1555-63, (2013)

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Abstract

A series of new, halogen containing N-substituted 4-aminobenzenesulfonamides were synthesized by using superacid HF/SbF5 chemistry and investigated as inhibitors of several human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, that is, the cytosolic hCA I and II and, the tumor-associated transmembrane isoforms hCA IX and XII. Despite the substitution of the sulfonamide function, the presence of fluorine atom(s) in β position of the sulfonamide function strongly favors hCA inhibition. A similar effect of the β-fluorinated alkyl substitution on the amino function has been also observed. Among the tested compounds, several chlorinated derivatives have been identified as selective nanomolar, tumor-associated isoforms inhibitors. These non-primary sulfonamides probably bind in the coumarin-binding site, at the entrance of the cavity, and not to the metal ion as the primary sulfonamide inhibitors.Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.