Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 21, Issue 6, Pages 1555-1563Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2012.05.037
Keywords
Hypoxic tumors; Superacid; Fluorine chemistry; Benzenesulfonamide; Halogen effect
Funding
- FP7 EU grant (METOXIA)
- CNRS
- University of Poitiers
- Region Poitou-Charentes
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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 beta position of the sulfonamide function strongly favors hCA inhibition. A similar effect of the beta-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 (C) 2012 Published by Elsevier Ltd. All rights reserved.
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