Inhibition of Carbonic Anhydrases with Glycosyltriazole Benzene Sulfonamides

Title
Inhibition of Carbonic Anhydrases with Glycosyltriazole Benzene Sulfonamides
Publication Date
2008
Author(s)
Wilkinson, Brendan
( author )
OrcID: https://orcid.org/0000-0003-1866-6540
Email: bwilkin7@une.edu.au
UNE Id une-id:bwilkin7
Innocenti, Alessio
Vullo, Daniela
Supuran, Claudiu T
Poulsen, Sally-Ann
Type of document
Journal Article
Language
en
Entity Type
Publication
Publisher
American Chemical Society
Place of publication
United States of America
DOI
10.1021/jm701426t
UNE publication id
une:23151
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 B-D-ribofuranosyl triazole 15 and α-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.
Link
Citation
Journal of Medicinal Chemistry, 51(6), p. 1945-1953
ISSN
1520-4804
0022-2623
Start page
1945
End page
1953

Files:

NameSizeformatDescriptionLink