Inhibition of membrane-associated carbonic anhydrase isozymes IX, XII and XIV with a library of glycoconjugate benzenesulfonamides.

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Title Inhibition of membrane-associated carbonic anhydrase isozymes IX, XII and XIV with a library of glycoconjugate benzenesulfonamides.
Author Wilkinson, Brendan Luke; Bornaghi, Laurent; Houston, Todd Ashley; Innocenti, Alessio; Vullo, Daniela; Supuran, Claudiu T.; Poulsen, Sally-Ann
Journal Name Bioorganic & Medicinal Chemistry Letters
Editor D.L. Boger, L. Ghosez and M. Shibasaki
Year Published 2007
Place of publication Oxford, UK
Publisher Pergamon Press
Abstract A library of glycoconjugate benzenesulfonamides that contain diverse carbohydrate-triazole tails were investigated for their ability to inhibit the enzymatic activity of the three human transmembrane carbonic anhydrases (CAs) isozymes hCA IX, hCA XII and hCA XIV. These isozymes have their CA domains located extracellularly, unlike the physiologically dominant hCA II, and are of immense current interest as druggable targets. Elevated expression of isozymes IX and XII is a marker for a broad spectrum of hypoxic tumors - this physiology may facilitate a novel approach to discriminate between healthy cells and cancerous cells. Many of these glycoconjugates were potent inhibitors (low nM), but importantly exhibited different isozyme selectivity profiles. The most potent hCA IX inhibitor was the glucuronic acid derivative 20 (Ki = 23 nM). This compound was uniquely hCA IX selective cf. all other isozymes (16.4-fold, 16.8-fold and 4.6-fold selective against hCA II, XII and XIV, respectively). At hCA XII there were many inhibitors with Kis<10 nM that also demonstrated excellent selectivity (up to 344-fold) against other isozymes. Potent hCA XIV inhibitors were also identified, several with Kis~10 nM, however no hCA XIV selective derivatives were evidenced from this library. The sugar tails of this study have therefore shown promise as a valuable approach to both solubilize the aromatic sulfonamide CA recognition pharmacophore and to deliver potent inhibition and isozyme differentiation of the transmembrane CAs.
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Copyright Statement Copyright 2007 Elsevier. This is the author-manuscript version of this paper. Reproduced in accordance with the copyright policy of the publisher. Please refer to the journal's website for access to the definitive, published version.
Volume 17
Page from 987
Page to 992
ISSN 0960-894X
Date Accessioned 2008-01-22
Language en_AU
Research Centre Eskitis Institute for Drug Discovery; Institute for Glycomics
Faculty Faculty of Science, Environment, Engineering and Technology
Subject PRE2009-Biological and Medical Chemistry
Publication Type Journal Articles (Refereed Article)
Publication Type Code c1

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