Inhibition of Carbonic Anhydrases with Glycosyltriazole Benzene Sulfonamides

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Wilkinson, Brendan L
Innocenti, Alessio
Vullo, Daniela
Supuran, Claudiu T
Poulsen, Sally-Ann
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Dr. Philip S Portoghese (Editor-in-Chief), Laurence H Hurley (Senior Editor), Yusuf J Abul-Hajj (Sen

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2008
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Abstract

A library of glycoconjugate benzene sulfonamides have been synthesized and investigated for their ability to inhibit the enzymatic activity of physiologically relevant human carbonic anhydrase (hCA) isozymes: hCA I, II, and tumor-associated IX. Our synthetic strategy directly links the known CA pharmacophore (ArSO2NH2) to a sugar "tail" moiety through a rigid 1,2,3-triazole linker unit using the Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction or "click chemistry". Many of the glycoconjugates were potent CA inhibitors and exhibited some isozyme selectivity. In particular, the methyl-d-glucuronate triazoles 6 and 14 were potent inhibitors of hCA IX (Kis 9.9 and 8.4 nM, respectively) with selectivity also favoring this isozyme. Other exceptional compounds included the deprotected ߭d-ribofuranosyl triazole 15 and a-d-mannosyl triazole 17, which were potent and selective hCA II inhibitors (Ki 7.5 nM and Ki 2.3 nM, respectively). Collectively, the results confirm that modification of ring size, stereochemical configuration, and chain length in the sugar tail moiety of glycoconjugate CA inhibitors permits tunable potency and selectivity that may constitute an important avenue for the future development of efficacious and selective CA-based therapeutics.

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Journal of Medicinal Chemistry

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51

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6

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© 2008 American Chemical Society. Self-archiving of the author-manuscript version is not yet supported by this publisher. The contents of this journal can be freely accessed online via the ACS web page. Use hypertext link above to access the ACS website.

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Medicinal and biomolecular chemistry

Organic chemistry

Pharmacology and pharmaceutical sciences

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